A BMW X5 and a Renault Kangoo van collided at the roundabout junction with Vendee Drive, adjacent to Bicester Village Park and Ride carpark, at around 8.15pm.
The driver and passenger in the Renault van, a 77 year old man and 80 year old woman, died at the scene.
The BMW had travelled on the A34 joining the A41 at junction 9 of the M40 – the driver and passenger sustained minor injuries and have since been discharged from hospital.
Next of kin have been informed.
Investigating officer Sergeant Phil Hanham of the Serious Collision Investigation Unit, said: “This was a very serious incident which has sadly resulted in the death of two people.
“We would like to speak to anyone who either witnessed the collision or saw the vehicles before this incident.
“We would also like any drivers or cyclists in the area at the time with dash-cam footage to check if these vehicles are present to assist with the investigation.”
Anyone with information should contact Thames Valley Police on 101 quoting reference 43190177431 or make a report online.
Alternatively call the independent charity Crimestoppers anonymously on 0800 555 111.