The driver of the other car, a 49-year-old man, was taken to a hospital in guarded but stable condition, police said.
The 23-year-old driver in a 2008 Honda was heading east in the westbound lanes of the LIE just east of Exit 41 at 4:16 a.m. when the Honda hit a 2012 Mercedes-Benz that was traveling west, police said.
The Honda then struck the median before stopping in the HOV lane.
The Mercedes spun around from the collision, coming to a halt in an adjacent exit ramp west of the crash.
The Honda driver was pronounced dead at the scene at 4:30 a.m. Police said they are withholding his name pending notification of his family.
Det. Sgt. Stephen Fitzpatrick said it appeared that the Honda entered the LIE the wrong way at the expressway's entrance, but the reason was undetermined.
The 24-year-old woman passenger in the Honda had to be cut free from the vehicle. She suffered internal injuries and was taken to Nassau University Medical Center in critical condition.
Both vehicles were impounded for safety checks.
The crash and the subsequent investigation shut down all westbound LIE lanes for nearly seven hours Sunday morning.
Early last year, in response to an alarming number of wrong-way DWI arrests -- at least 16 between November 2010 and January 2011 -- state officials began re-examining roadway signs across Long Island and elsewhere in the state. One arrest involved the death of a veteran NYPD officer, killed, police say, when his car was struck head on by a drunken driver moving in the wrong direction on the Northern State Parkway.
Police said the investigation into Sunday's crash is ongoing.
With Scott Eidler