The 52 prisoners who are being freed over the next few months are the last remaining jailed members of the group of 75 opposition figures arrested in a mass government crackdown in 2003.
The Cuban authorities have long denied that they hold political prisoners, calling them mercenaries paid by the United States to undermine the system.
But this mass release is being seen as a major concession to international pressure over human rights, and could have positive ramifications in terms of improved relations with both the US and Europe.
The case of the "75" had long soured the European Union's relations with Cuba.
Initially, the EU imposed sanctions following their arrest, though these were later suspended. At Cuba's insistence they were finally removed in 2009, but only on the condition that there should be an annual review of this one-party state's human rights record.
Spain had hoped to use its presidency of the EU to press for the review to be abandoned, but the death of the jailed dissident hunger striker Orlando Zapata in February made that impossible.
His death brought widespread international condemnation, refocusing attention on Cuba's human rights record and political prisoners. It also emboldened dissident groups inside Cuba.
A second hunger striker, Guillermo Farinas, is currently in a critical condition in hospital on a drip-feed.
These prisoner releases will be the largest since 1998, when 101 political prisoners were freed as part of a broader amnesty following the visit of Pope John Paul II.
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