Police were called to the incident on the A259 Gravetts Lane, Climping, near Littlehampton at around 5.30pm on Tuesday.
The crash involved four cars: a silver and black Mitsubishi L200, a white Volkswagen Transporter, a silver Vauxhall Corsa and a silver Nissan Juke.
The driver of the Mitsubishi, a 26-year-old man, and the driver of the Nissan Juke, a 60-year-old woman, were both taken to hospital with serious injuries, where they remain.
No other injuries were reported.
The road was closed for several hours for recovery and collision investigation but has since reopened.
A spokesman for Sussex Police said: “We are investigating the collision and anyone who witnessed the incident or has dash cam footage is asked to contact police.
“Information can be reported to Sussex Police online or emailed to collision.appeal@sussex.police.uk quoting Operation Beckett.”
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