It is thought two people were killed in a three vehicle pile-up near Tankersley.
Fire crews and police were called to the scene at about 6.20am on Wednesday.
Cutting equipment was used to remove the injured. A fire service spokesman said it was suspected that two were dead.
Police issued an appeal saying the force was 'desperate' for witnesses to the collision, which occurred on the A616 Stocksbridge bypass, about a mile away from Tankersley roundabout.
The vehicles involved were a van travelling towards Sheffield and a van and a car travelling from Sheffield.
The road was closed but is expected to reopen before 11.30am.
A police spokesman said: "We are desperate for witnesses who saw the accident or saw anything in the moments leading up to it.
"It's a busy stretch of road and we know there were vehicles there that didn't stop at the scene."
Call police on 0114 2202020.
