A statement from police did not say if the pursuit was still active or had been called off when the allegedly stolen car crashed into the truck at Bell Street.
The truck’s trailer fell onto its side and hit an Audi sedan, which was stationary at the intersection.
The two occupants of the allegedly stolen car died at the scene, while the drivers of the truck and Audi were taken to hospital.
Ambulance Victoria said a man in his 30s was taken to the Royal Melbourne Hospital in a stable condition with chest injuries.
Another man was taken to the Austin Hospital, also in a stable condition.
Bell Street was closed in both directions between St Georges and Plenty roads on Wednesday morning. High Street was closed in both directions between Gower and Raglan streets.
Bus route 513 was being diverted via Murray Road, however trams on Plenty Road were not expected to be affected.
The Transport Department said drivers should consider using Murray or Darebin roads instead of Bell Street. Commuters heading towards the city could still use St Georges Road or Plenty Road.
The investigation will be overseen by Professional Standards Command because the crash involved a police pursuit.
Investigators want anyone who may have seen the crash or has dash cam footage to contact Crime Stoppers on 1800 333 000 or file a confidential report at www.crimestoppersvic.com.au.
Zach is a reporter at The Age. Got a story? Email me at email@example.com