It happened at around 3:30 a.m. on southbound 101 just north of the 580 interchange.
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A pick-up truck heading northbound crashed head-on in a black BMW.
Authorities believe alcohol was a factor.
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The pick-up driver, a 22-year-old man from Santa Rosa, was pronounced dead at the scene, authorities said.
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The driver in the BMW, a 30-year-old man from Novato, sustained major injuries and is currently at Marin General Hospital.
He was later identified as Trey King.
King's father told ABC7's Liz Kreutz his son was on his way to work at the Oakland airport.
He says he underwent surgery and has more scheduled on Sunday.
All lanes have reopened after they were shut down for nearly three hours.