The crash happened at 2.55PM yesterday on Friarage Road - where a Nissan car collided with a Honda.
It has not been established what caused the accident, and an investigation has now opened.
Both drivers and passengers were taken to Stoke Mandeville Hospital.
Thames Valley Police is now appealing for witnesses.
It happened yesterday (2/1) at around 2.25pm on the A41, Friarage Road.
A red Honda car was in a collision with a grey Nissan car.
The road was closed for around two and a half hours to allow emergency services access to the scene.
Sadly, the driver of the Honda, a 53-year-old man, died at the scene.
His next of kin has been told and they are being supported by officers.
Two further passengers, two women, from the Honda sustained non-life threatening injuries and were taken to the Stoke Mandeville Hospital for treatment.
Two people in the Nissan were not injured.
An investigation has now started to establish exactly what led to the collision.