Police say that a 48-year-old woman from Pulborough suffered ‘serious head and arm injuries’ in the accident on the southbound carriageway of the A29 near Adversane Lane just before 1pm.
The woman, who was driving a Toyota Yaris, was cut free from her car before being airlifted to the Royal Sussex County Hospital in Brighton.
Police say that another woman, a 69-year-old passenger in a Citroen C1, also suffered serious injuries and was also taken to Brighton hospital.
The driver of the Citroen, a 69-year-old man from Pulborough, was treated at Worthing Hospital for slight injuries.
Officers say that another man, a 52-year-old van driver from Lavant, was also slightly injured and was treated at St Richard’s Hospital in Chichester.
A police spokesman added: “Drivers of the other cars were unhurt.”