The crash happened at around 10am this morning eastbound near the junction of Shellbridge Road, west of Arundel.
A man in his 80s was taken to hospital in a serious condition.
The crash involved a BMW and Suzuki which were both badly damaged.
The A27 from Fontwell is currently closed eastbound with a diversion in place on the A29.
A Sussex Police spokesman said: “Please make alternative journeys while services continue to work in the area.
“Anyone who witnessed the incident or has dashcam footage is urged to come forward and make a report.
“You can contact us via our online reporting form or by calling 101 quoting Operation Mitchell.”
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