Two boys, aged four and 10, and a 32-year-old woman died after the car they were travelling in overturned at around 11.30am.
Two other women who were also in the car at the time of the accident were receiving treatment in hospital last night. Their injuries were not thought to be life-threatening.
The cause of the crash, which happened on the Northbound carriageway near junction 15 close to Stoke, is not known.
Heavy rain has hit large areas of the country in recent days but the Highways Agency said conditions were fine and dry at the time of the accident.
Three ambulances, three paramedic officers, a doctor and two Midland Air Ambulances rushed to the scene but were unable to save the two boys and the woman.
A West Midlands Ambulance Service spokesman said: “Crews arrived to find a single vehicle that had crashed and overturned.
“Two children and an adult that were travelling in the vehicle suffered serious injuries.
“Unfortunately, despite the best efforts of ambulance crews, nothing could be done to save the two boys and one woman, and they were confirmed dead at the scene.
“Two other adult women travelling in the car, both received emergency treatment at the scene for their injuries and were transferred by land ambulances to University Hospital North Staffordshire on blue lights for further treatment.
“All emergency services personnel worked seamlessly together at the scene in exceptionally difficult circumstances.
“Unfortunately, the outcome was not the one everyone would have hoped for.”
It was initially reported three children had been killed in the accident but this was later revised by emergency services.
No further information on the identities of those involved was released.
Meanwhile, two people were killed and a third person was left with serious injuries following another car crash in Hampshire.
Police were called at shortly after 10am after receiving a report that a car had been involved in a collision on the B3349 Odiham Road near Basingstoke.
Two people in the car were pronounced dead while a man who was believed to be the driver of the vehicle, received medical attention at the scene before being taken to hospital with serious injuries.
Next-of-kin have been informed.