Cuba's President Raul Castro and his Venezuelan counterpart Hugo Chavez are signing economic co-operation deals worth $3.2bn (£1.96bn).
The documents cover 285 accords in areas including energy, sport and technology.
The new deals will give Venezuela a greater involvement in oil exploration off the Cuban coast.
Cuba also agrees to buy more than $400m (£246m) worth of Venezuelan goods, including food, tyres and clothes.
The BBC's correspondent in Havana Michael Voss says the agreement will provide an economic lifeline to the communist-run island.
'Historic'
The signing comes a day before Cuba hosts a summit of the regional political and economic bloc, the Bolivarian Alliance for the Peoples of America (Alba), which was founded by the two nations five years ago as a radical alternative to America's free trade policies in the region.
Our correspondent says there is speculation that Fidel Castro may attend the summit.
The 83-year-old met President Chavez on Saturday but has not been seen in public for three-and-a-half years.
Mr Castro said the agreements were "historic".
Our correspondent says the deals also underscore Venezuela's role as Cuba's closest political and commercial ally and comes as Raul Castro struggles to cope with the global economic crisis.
The island has suffered a sharp decline its revenues from tourism as well as mineral and tobacco exports.
Venezuela - an Opec member - is already an important source of energy and trade to the Caribbean island, which repays part of its oil bill by providing the services of 40,000 professional workers.
Last year trade between the two countries was at around $5.26bn (£3.23bn) last year, the Reuters news agency reported.
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