The accident happened at I-40 and Jones Sausage Road at 2:20 a.m.
According to an accident report, 28-year-old Carolina Gonzales Linares was driving her Toyota the wrong way on I-40 northbound at 65 mph when she hit a Ford minivan head-on.
An eyewitness told ABC11 that he saw a car traveling in the left lane heading toward oncoming traffic without its lights on. The car then slammed head-on into the vehicle driving behind him.
A driver first notified police that there was a wrong-way driver on I-40 Westbound at exit 298A, nearly six miles from the site of the crash.
Police said 21-year-old Natanael Hernandez was driving the minivan and his brother, 17-year-old Job Hernandez, was in the passenger seat.
"They were returning from Jacksonville," the brother's uncle, Kris Ramsundar, said. "Natanael was visiting his girlfriend and they were coming back late. They had a meal, and spent some time with his girlfriend's family."
Linares and Job Hernandez died at the scene, while Natanael Hernandez was critically injured and taken to WakeMed. Officers said all three were wearing seatbelts at the time of the crash and were trapped inside the cars.
Job would have been a rising junior at Enloe High School in Raleigh this fall.
"Job was extremely talented. He could play anything he put his hands on, taught himself to play the piano. And whatever other instruments he got his hands on, that's what he played," Ramsundar said.
On Monday, his family was at the hospital with Nathanael, waiting for word from police investigating the accident.
"The first thing you think is that a drunk driver might be involved, going the wrong way. And it is a tragedy," Ramsundar said.
There's no word yet on any link to alcohol -- toxicology results won't be complete for several weeks.
In the meantime, Ramsundar told ABC11 that the father of both young men said his thoughts and prayers are also with ... "the family that lost a daughter, or a wife. He is very concerned for them also, and his condolences go out to them."