The A27 Brighton bypass was closed after a lunchtime crash involving two vans and a lorry.
The accident happened just before 1pm between the A23 turn-off at Patcham and where traffic joins from the A270 Lewes Road.
The road was still closed eastbound more than three hours later with Sussex Police issuing a warning to drivers just before the evening rush hour.
The force said: “Police are warning drivers about significant delays on the A27 near Brighton on the busiest Friday of the year (19 December).
“Emergency services are on scene at a collision involving two vans and a lorry on the A27 eastbound between the A23 at Patcham and the A270 at Lewes Road at shortly before 1pm.
“The road was closed in both directions for a short time while the air ambulance landed.
“The westbound carriageway has reopened but the eastbound carriageway is still closed. There are significant delays on the A27 eastbound and A23 southbound.
“The driver of a transit van has taken to the Royal Sussex County Hospital with serious but not thought to be life-threatening injuries in a land ambulance.
“The driver of the lorry was also taken to the Royal Sussex with slight injuries.
“Recovery is currently on the way to the scene.”
Superintendent Jane Derrick said: “We are working as quickly as we can to clear the vehicles and get the A27 reopen again.
“We are asking motorists to try and avoid the area as much as possible and try and find alternative routes for their journey.
“We know the roads will be very busy but remind people to drive carefully and take extra time to travel to where they need to go.”
This morning three crashes in 30 minutes caused widespread traffic congestion north of Brighton.
At 7.46am police were called to the A23 at its junction with the A273 at Pyecombe where six vehicles had been involved in a smash, blocking two lanes on the northbound side of the road.
No one was hurt and all lanes were clear by 8.30am.
At 8.13am two of the three lanes on the northbound side of the A23 were blocked at Handcross after a crash involving two cars. No injuries were reported.
And at 8.16am a car span off the A27 at Hollingbury. No one was hurt and Sussex Police said that traffic was not disrupted in this instance.
The force said: “Long queues built up on the approaches to the various crash scenes while emergency services worked to get traffic flowing again.”
UPDATE Sussex Police said that the A27 Brighton bypass had fully reopened just before 5pm.