The 22-year-old "has completed his journey home," relatives said in a statement. They did not cite a specific cause of death.
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"Unfortunately, the awful, torturous mistreatment our son received at the hands of the North Koreans ensured that no other outcome was possible beyond the sad one we experienced today," his parents said.
Doctors had described his condition as a state of "unresponsive wakefulness" and said he suffered a "severe neurological injury" of unknown cause.
His father, Fred Warmbier, said last week that he believed Otto had been fighting for months to stay alive to return to his family. Their statement Monday said he looked uncomfortable and anguished after arriving June 13, but his countenance later changed.
"He was peace. He was home, and we believe he could sense that," they said.
Warmbier was convicted of subversion for allegedly trying to steal a propaganda banner while visiting with a tour group. He was put before North Korea officials and journalists for a televised "confession."
"I have made the worst mistake of my life!" he exclaimed, choking up as he begged to be allowed to reunite with his parents and two younger siblings. He was sentenced to 15 years in prison with hard labor.
The University of Virginia student was held for more than 17 months. His family said they were told he had been a coma since soon after his March 2016 sentencing.
Doctors said he suffered extensive loss of brain tissue and "profound weakness and contraction" of his muscles, arms and legs. His eyes opened and blinked but without any sign that he understood verbal commands or his surroundings.
Unresponsive wakefulness is a new medical term for persistent vegetative state. Patients in this condition who have survived a coma can open their eyes, but they do not respond to commands. People can live in a state of unresponsive wakefulness for many years with the chances of recovery depending on the extent of the brain injury.
North Korea said Warmbier went into a coma after contracting botulism and taking a sleeping pill. Doctors in Cincinnati said they found no active sign of botulism or evidence of beatings.
His parents told The Associated Press in a statement the day of his release that they wanted "the world to know how we and our son have been brutalized and terrorized by the pariah regime."
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Fred Warmbier praised his son's "performance" and President Donald Trump's administration. He was critical of the approach to his son's situation taken by former President Barack Obama's administration.
In a White House statement, Trump said, "Lot of bad things happened, but at least we got him home to be with his parents." He called North Korea a "brutal regime."
The younger Warmbier grew up in the Cincinnati suburb of Wyoming. He was salutatorian of his 2013 class at a highly rated high school, and was on the soccer team, among other activities.
He had had planned to study in China in his third year of college and heard about Chinese travel companies offering trips to North Korea.
Young Pioneer Tours described itself as providing "budget tours to destinations your mother would rather you stayed away from." Its travel options also included Iran, Iraq and former Soviet countries.
Warmbier was in the process of leaving North Korea on Jan. 2, 2016, when he was detained at the airport.
The State Department warns against travel to North Korea. While nearly all Americans who have been there have left without incident, visitors can be suddenly seized and face lengthy incarceration for what might seem like minor infractions.
Jeffrey Fowle, also from Ohio, was detained in 2014 when he intentionally left a Bible in a night club. Fowle was freed after six months. He said he was kept isolated most of the time but not physically abused. He and others freed from North Korea have said they were coached and coerced into giving confessions.
Three Americans remain held in North Korea. The U.S. government accuses North Korea of using such detainees as political pawns. North Korea accuses Washington and South Korea of sending spies to overthrow its government.
At the time of Warmbier's release, a White House official said Joseph Yun, the U.S. envoy on North Korea, had met with North Korean foreign ministry representatives in Norway the previous month. Such direct consultations between the two governments are rare because they do not have formal diplomatic relations.
Yun learned about Warmbier's condition in a meeting a week before the release from the North Korean ambassador at the U.N. in New York. Yun then was dispatched to North Korea and visited Warmbier June 12 with two doctors and demanded his release on humanitarian grounds.
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His hometown had rallied around his family, wrapping school-color ribbons around trees and utility poles lining Wyoming's main road. People chanted "Otto Strong!" and "We love you!" after his father's news conference last week at the high school.
Warmbier was "generous, outgoing, sweet, smart as a whip, just an overall good guy," Danica White, his sophomore English teacher, recalled last week. He brought "this brightness" and excitement to the classroom.
On Monday evening, she said: "Otto will be dearly missed."
FULL STATEMENT FROM FAMILY
"It is our sad duty to report that our son, Otto Warmbier, has completed his journey home. Surrounded by his loving family, Otto died today at 2:20pm.
"It would be easy at a moment like this to focus on all that we lost - future time that won't be spent with a warm, engaging, brilliant young man whose curiosity and enthusiasm for life knew no bounds. But we choose to focus on the time we were given to be with this remarkable person. You can tell from the outpouring of emotion from the communities that he touched - Wyoming, Ohio and the University of Virginia to name just two - that the love for Otto went well beyond his immediate family.
"We would like to thank the wonderful professionals at the University of Cincinnati Medical Center who did everything they could for Otto. Unfortunately, the awful torturous mistreatment our son received at the hands of the North Koreans ensured that no other outcome was possible beyond the sad one we experienced today.
When Otto returned to Cincinnati late on June 13th he was unable to speak, unable to see and unable to react to verbal commands. He looked very uncomfortable - almost anguished. Although we would never hear his voice again, within a day the countenance of his face changed - he was at peace. He was home and we believe he could sense that.
"We thank everyone around the world who has kept him and our family in their thoughts and prayers. We are at peace and at home too.
"-Fred & Cindy Warmbier and Family"