OPP say that the driver of a passenger car was southbound on Highway 41 and crossed the centre line, striking the northbound SUV driver.
The pick-up truck driver that was following the SUV swerved to avoid the collision, striking the guardrail.
The driver of the passenger car was trapped and required extraction from the vehicle by the Fire Department. They were airlifted to a hospital with life threatening injuries.
The remaining two drivers were transported to hospital by paramedics with minor injuries.
The highway was closed for several hours to investigate while OPP technical Collision Investigators (TCI) remained on scene.
Police were assisted by members of the Bonnechere Valley Fire Department and Renfrew County Paramedics.
The collision remains under investigation.
Police are asking anyone with information to contact the Killaloe/ Renfrew OPP or Crime Stoppers anonymously at 1-800-222-TIPS or www.valleytips.ca.