Victoria Police believe a 72-year-old Honda station wagon driver travelling on the Eastern Freeway may have had a medical episode before exiting the freeway at Chandler Highway about midday today.
It crashed into the rear of a stationary Hyundai station wagon waiting at traffic lights.
The impact of the crash caused the Hyundai to push forward and was struck by a Mitsubishi hatchback and a Honda sedan.
The Hyundai driver, a Glen Waverley man, suffered life-threatening injuries in the crash and was taken to hospital.
His passenger, a 29-year-old woman, was not injured.
The 72-year-old Honda driver was taken to hospital with minor injuries. His passenger, an 84-year-old woman, was taken to hospital with serious injuries.
The driver of the Honda sedan and her two female passengers were uninjured.