A Honda motorhome and a Ford Fiesta collided on the A619 in Baslow between the Robin Hood Inn pub and the Golden Gates roundabout at about 8.30am.
A Derbyshire police spokesman said: “Four people were injured, two seriously.
“They have been taken to the Northern General Hospital in Sheffield.”
The road, which was closed to allow for the removal of debris and fluid, has now reopened.
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The road closure caused widespread congestion in the area.