"We find ourselves in the midst of a global crisis," said Sen. Chris Dodd, D-Conn. "What we've been missing in all of this is the head of the Health and Human Services Department."
Sixty votes in the 100-seat Senate were necessary for approval.
Immediately after the vote Sebelius resigned as governor in Kansas and headed to Washington to be sworn in. She drove directly from Andrews Air Force Base in Maryland to the White House, where she took her oath in the Oval Office.
"We wanted to swear her in right away because we've got a significant public health challenge that requires her immediate attention," Obama said, standing beside the last Cabinet official to win Senate approval.
"We needs all hands on deck," he said. "I expect her to hit the ground running," Sebelius immediately went to the White House's Situation Room for a briefing with Obama's homeland security adviser, John Brennan, and other officials dealing with the first domestic test of the administration, which turns 100 days old on Wednesday.
Replacing Sebelius as the state's chief executive was the lieutenant governor, Mark Parkinson, 51, a former Republican lawmaker and state party chairman Sebelius had persuaded to be her running mate in 2006. Parkinson has said he plans no major policy or staff changes and wouldn't run for a full term next year.
Republican opponents cited Sebelius' pro-abortion stances and her initial underreporting of campaign contributions from a late-term abortion doctor. They raised concerns about whether Obama administration plans to overhaul the nation's health system would cut out Republicans and lead to rationing of care.
"She is the wrong appointee for this particular assignment," said Sen. Robert Bennett, R-Utah. "She has backed a partisan process for health care reform. She has refused to support patient safeguards."
With no HHS secretary in place, the White House has turned to Homeland Security Secretary Janet Napolitano to help lead its response to the swine flu, even while insisting that vacancies at the top of HHS were not a problem.
Sebelius, 60, a two-term Democrat, was the first of 20 HHS officials requiring Senate approval to win it, and she heads to work with many team members missing. The Senate hasn't acted on Obama's nominees for deputy HHS secretary or commissioner of the Food and Drug Administration, and Obama hasn't even nominated people for other key jobs, including surgeon general and assistant secretary for preparedness and response.
There's also not been an appointment for head of the Centers for Disease Control and Prevention, another component of the sprawling HHS, which has 65,000 employees and a $750 billion budget.
The whole process suffered a setback when Obama's first pick for HHS secretary, former Sen. Tom Daschle of South Dakota, withdrew in February over unpaid taxes.
Though the swine flu will be an immediate focus, Sebelius will also be charged with shepherding Obama's overhaul of the nation's $2.5 trillion health care system to reduce costs and cover some 50 million uninsured Americans.
