The collision happened around 11:30 a.m. PT on Kingsway near Olive Avenue. Kingway is expected to remain closed to traffic in all directions for several hours, police said.
Police say the car's second occupant is being treated for serious life-threatening injuries while the woman was confirmed dead at Vancouver General Hospital.
RCMP Cpl. David Reid says investigators are trying to figure out the cause of the crash.
"There's a possibility that a pre-existing medical condition made its presence known, shall we say, and that either resulted in the accident or it was a product of the accident," he said.
The transit bus driver was taken to Royal Columbian Hospital with serious injuries and at least three bus passengers were transported to Burnaby General Hospital with less serious injuries.