Five males were in the car travelling on the southbound carriageway of the A419 when it was in collision with a lorry exiting the Castle Eaton junction.
Two males were taken to Southmead Hospital, Bristol, by land ambulance with life threatening/changing injuries. The other three were taken to GWH, Swindon, with lesser injuries.
The male lorry driver was also taken to the GWH with minor injuries.
The southbound carriageway of the A419 is completely closed from the Cricklade junction towards Swindon; one lane northbound, close to the road traffic collision, is also closed.
Traffic is at a standstill on the southbound carriageway and very slow on the northbound carriageway.
Acting Inspector Louis McCoy said: "Tri-force officers are investigating this collision and are carrying out a detailed examination of the road, as a result this part of the A419 will be closed for the next three to four hours.
"I'd like to thank motorists caught up in any delays for their patience and would advise anyone travelling in and around Swindon to avoid this area of the A419 for now. "
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