Flames shot into the air along the roadway near 165th Street as traffic came to a standstill just before 2:30 a.m.
Officials say the driver of a pickup truck was driving south in the northbound lanes when it hit a Dodge sedan.
A 40-year-old man was taken to Harlem Hospital and a 38-year-old man was taken to Columbia Presbyterian Hospital.
They had both been in the sedan and both were pronounced dead at the hospital.
Two people inside the pickup truck ran from the scene.
A 22-year-old passenger was later caught and was being questioned by police.
Northbound lanes remained closed near 178th Street as crews continued their investigation.
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