Pedro Sanchez on Thursday kicks off the first official visit by a Spanish leader to Cuba in 32 years, as Havana seeks closer ties with the European Union faced with a hardline United States.
Sanchez's Socialist government said his two-day trip will end the "anomaly" that no Spanish leader has paid an official visit to the communist island since 1986, despite Spain being Cuba's second biggest trading partner after Venezuela.
Other world leaders have visited Cuba in recent years, including US president Barack Obama's historic 2016 trip as he sought to thaw relations with Havana.
But relations between the two countries have declined under President Donald Trump.
The US has maintained its decades-long economic blockade of Cuba, citing repression of political opponents and curbs on freedom of expression.
It has also accused Cuba of being behind mysterious sonic "attacks" on US diplomats in the country who have suffered symptoms consistent with mild brain trauma -- including, in some cases, disorientation and hearing loss.
Cuba has rejected those accusations.
As relations with Washington have soured, Havana has sought new allies in the EU.
Sanchez's visit comes just days after EU and Cuban officials met as part of a landmark cooperation deal that took effect in November 2017.
Sanchez is due to meet with Cuban president Miguel Diaz-Canel but is not expected to hold talks with Raul Castro, who stepped down as president in April but still leads the ruling Communist Party.
Sanchez will host a breakfast gathering with Spanish business leaders and a forum for which some 200 companies from both countries have registered, including telecoms giant Telefonica or the airline Iberia.
Spain is the main foreign investor in several sectors of the Cuban economy, including tourism and financial services.
It hopes to increase its presence in tourism, renewable energy and infrastructure as the island opens up, the Spanish government said.
Cuba is also keen for foreign investment as its economy suffers from a crisis in Venezuela, its biggest trading partner and oil provider.
Sanchez will also broach the thorny issue of recent unpaid debt from Cuba to Spain, which is blocking loan concessions.
He is not expected to meet with dissidents, according to the Spanish government, but will hold talks with members of Cuba's civil society, including Cuban writer Leonardo Padura and designer Idania del Rio.