Emergency services are currently at the scene of the collision which happened on the B2133 road in Newpound Common, west of Billingshurst, just after 4pm.
The road is currently closed while investigations take place.
One casualty has been airlifted to St George’s Hospital in London and three have sustained critical injuries, said police.
A spokesman said: “All three emergency services are at the scene. Three people in one vehicle suffered critical injuries and a fourth suffered minor injuries.
“One has been airlifted to St Georges Hospital in London, while two have been taken to hospital by road ambulance. A fourth has been taken to Worthing Hospital.
“Another person travelling in another vehicle suffered minor injuries and has been taken to Worthing Hospital.
“The B2133 remains closed while investigations continue at the scene and is likely to be closed for some time.
“Police want to thank members of the public for their patience.”