Police have confirmed four cars and a lorry were involved in two crashes which happened at 01:00 BST between J8 and J9 southbound.
The 24-year-old driver of a Mercedes car and 23-year-old passenger, both from Gloucester, died in the second crash.
Two other 23-year-old men, who were passengers in the car, are in critical condition in hospital.
The carriageway was closed down for 11 hours between the two junctions.
Police have said the first crash was between a Ford Mondeo and a MG Rover, south of the M50 junction.
A Force Spokesman said: “A HGV then stopped and was involved in a collision with a silver Mercedes and black Mazda
“Two occupants from the Mercedes died at the scene and a further two occupants were seriously injured – one was taken to Queen Elizabeth Hospital in Birmingham and one to Southmead Hospital in Bristol.”
Four other people from other vehicles that were involved in the collision were assessed and treated by South Western Ambulance Service.
The southbound carriageway of the M5 was reopened after 11 hours.
Highways England said emergency crews from three different counties have been involved in the upshot.
