A severe flood warning was issued for the River Ouse at Lewes and emergency services are preparing for the worst.
Police have begun evacuating traders and homeowners as the river threatened to burst its banks for the second time since October.
A Sussex Police spokesman said: "The river is extremely high and we are taking appropriate precautions.
"Water is starting to pour down hills at the back of the town, the scenario that heradled the beginning of the October flood."
Residents in the town are being warned to expect the worst.
Peter Midgley, Sussex area manager for the Environment Agency, said: "The weather has dealt us yet another severe blow. We are yet again on a knife-edge."
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