Reports coming in from the area in Libourne, east of famous wine region Bordeaux, say that a lorry and a bus collided head on - with both vehicles then catching fire.
The force of the impact caused the vehicles to ignite, with the driver of the lorry also perishing in the blaze.
An official with the National Gendarme service in the town Puisseguin said that the high death toll is probably due to the fire.
Most of the dead are believed to be adults, according to French officials on the scene, and BBC reports have suggested that many of those on the bus were pensioners.
Only eight people survived the crash, with five of them sustaining injuries.
More than 60 firefighters attended the crash, which occurred on a country road at about 7.30AM french time.
And while the cause of the incident has not yet been determined, a local resident told a french publication that the area was a notorious crash spot.
President Hollande, who is abroad on state business, expressed his sadness over the incident, and said a ‘full investigation’ would take place.