RCMP say a female died after receiving surgery at a hospital in Vancouver. A second female also received surgery, and is in stable condition.
One person died at the scene of the crash, about 120 kilometres west of Prince George.
An SUV crossed the centre line, hitting a passenger car head-on, said RCMP spokesman Pat McTiernan.
A commercial truck and trailer then collided with the vehicles, and was rear-ended by a commercial crane unit.
McTiernan says investigators are trying to figure out why the SUV crossed the centre line.
"Investigators have got to examine everything from cell phones to road conditions to anything else that might have allowed that vehicle to cross over the centre line. So that's what they're focused on right now, and we're hopeful that that's going to come together."
The highway was closed for several hours after the crash.
McTiernan says the identities of the people who died aren't being released at this time, pending notification of family members.
Weather and road conditions are being considered as possible contributing factors.