The crash between a coach carrying 49 elderly people and a lorry occured early on Friday morning on a minor road near the village of Puisseguin in the wine-making Bordeaux area in south-west France.
The passengers were reportedly on an outing for the elderly.
The coach burst into flames after colliding head on with the lorry, whose driver was among the dead.
Only eight people managed to escape from the blaze and five of them were injured.
The bend where the accident happened was known to be dangerous, local people told French media.
"The French government has fully mobilised after this terrible tragedy," President Francois Hollande said from Athens, where he is on an official visit.
Valls, Interior Minister Bernard Cazeneuve and Transport Secretary Alain Vidalies announced that the would visit the scene after the news broke.
This is the worst traffic accident in France since 1982 when 53 people, most of them children, died in a crash in Beaune in the Burgundy region of central France.
On Thursday eveing four people, including a couple and theiir eight-year-old daughter, died when a lorry ploughed into a traffic jam caused by another lorry overturning on the A1 motorway.