The motorway was closed in both directions for several hours following the collision, which happened on the northbound carriageway between junctions 10 and 11 shortly before 11.40pm on Saturday.
Police have confirmed a 60-year-old man from Oxfordshire and a 29-year-old man from Warwickshire died as a result of the crash.
The man with serious leg injures was taken to hospital and three others were treated for minor injuries.
One driver said he saw about 30 emergency vehicles at the scene, near Cherwell Valley services.
South Central Ambulance Service confirmed five crews were sent to the scene.
More follows...