The accident occurred shortly after 2:30 a.m. on westbound I-40 between the N.C. Highway 55 and Fayetteville Road exits in Durham County, police said.
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An eastbound Oldsmobile driven by Glenda James, 47, of Kannapolis, collided with a westbound Saturn driven by Stephen Schmits, 25, of Cary.
Both drivers were pronounced dead at the scene, and both vehicles were total losses, police said.
"Her car was going the wrong way on I-40 and smashed head-on into his vehicle. At this time, we don't know where she got on I-40 the wrong way, and we don't know why," said Kammie Michael, a spokeswoman for the Durham Police Department.
The accident shut down all westbound lanes for more than five hours, causing extensive delays during the morning rush hour, police said. Westbound I-40 was reopened at 8:15 a.m.
"We're looking into the possibility that either alcohol or speed may have been a factor in the accident. But right now, we're still in the preliminary stages of the investigation," Michael said, adding that police are looking for possible witnesses to the wreck.
"If (anyone) witnessed the accident, call us if (you) saw her going to the wrong way on the highway," she said.
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