The collision, which happened at about 10.30pm yesterday, involved a Vauxhall Astra and an Audi TT on the A1077 between South Ferriby and Barton.
Police said two men travelling in the Vauxhall Astra have died after the crash.
A spokesperson for Humberside Police added: "Another man suffered serious and potentially life-threatening injuries and a further two suffered serious injuries which are not thought to be life-threatening.
"A 23 year-old man who was the driver and sole occupant of the Audi TT suffered serious, but not life-threatening injuries."
The two men who died have not yet been formally identified.
The road was closed until 7.50am this morning.
Anyone with information is asked to call 101, and quote log 679 October 27.