The multi-vehicle crash on the Western Freeway at Myrniong near Bacchus Marsh happened just before 4pm on Monday.
Victoria Police said 14 vehicles were involved in one crash that happened with heavy fog in the area, while five other separate collisions took place in the surrounding area.
Ambulance Victoria confirmed paramedics responded to "several multi-vehicle incidents" at Myrniong with a total of 20 patients taken to hospital.
Two patients were taken to the Royal Melbourne Hospital, where one remained in a critical condition and the other in a serious condition as of Tuesday afternoon.Â
Police said the cause of the collisions appeared to be heavy fog in the area and drivers not driving to the conditions.
Road Policing Command Assistant Commissioner Glenn Weir said officers were frustrated people didn't adapt their driving to the fog.
"When you're on another freeway or another road and it's absolutely thick fog or pouring rain, you shouldn't need emergency services to tell you to slow down and adapt to the driving conditions," Mr Weir told reporters on Tuesday.
"We were quite fortunate at this stage that no one has lost their life."
Mr Weir said even more cars than thought could have been involved in Myrniong's mass collision, with some not stopping to report the incidents to police.
Because of that, officers did not know the true number of people involved in Monday's crashes, he said.
"The number of injured was really concerning, putting more pressure on Ambulance (Victoria) and the health system," Mr Weir said.
Fog in the area was unusual for December, he said.
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