No arrests had yet been made.
The victims were gunned down outside the Love Machine nightclub on the corner of Little Chapel Street and Malvern Road in Prahran early on Sunday morning.
Police believe multiple people were shot during the incident and say a 28-year-old man and another who is yet to be identified are in critical conditions.
A 50-year-old man and a 29-year-old man have non-life-threatening injuries.
Investigators were probing links to motorcycle gangs, The Age newspaper in Melbourne reported.
The shot people included two security guards and a patron. The auto then left the area via Chapel Street.
A reporter for 10 News First Melbourne, Kristina Costalos, tweeted an image of the scene of crime, saying: "This is now the scene outside "Love Machine" nightclub near Chapel Street".
Clothes on the ground outside the club.
Edie, who lives in the nearby commission flats, said she didn't hear anything overnight.
Five people were killed in Melbourne in four unconnected shootings in less than a fortnight.
Four people were taken to hospital after the shooting, but police believe others may have been injured and fled the area before emergency services arrived.
Those with video footage of the incident or information that could assist police with their investigation are urged to come forward and call Crime Stoppers on 1800 333 000 or make a confidential report online.