The Great Plague, also known as the Dark Plague was a disastrous pestilence that killed untold numbers of people that possibly went up into the hundreds of thousands. The plague was brought by an evil wind from the east.
The Great Plague began in the east beyond Mordor and first hit Rhûn and Rhovanion, and after it had passed more than half the folk of the Kingdom of Rhovanion had been killed. It reached Osgiliath in T.A. 1636 (just a year after King Minardil of Gondor had been killed at Pelargir by the Corsairs of Umbar). The new king, Telemnar was killed together with his kin and the White Tree of Gondor, as well as many others of the Dúnedain; two centuries after the Kin-strife, this further destroyed the people of Gondor.
The city of Osgiliath was especially hit hard, suffering the highest casualties outside of Rhovanion. Many fled the city and removed to Ithilien and Anórien, and Minas Anor became the King's seat. The casualties were so high that the fortresses guarding Mordor were abandoned as the troops were recalled.
From there the plague spread west and then north. Enedwaith and Dunland were scarcely affected, but the Plague regained strength as it went north, and Minhiriath (the southern part of Cardolan) was especially hit hard. The last of the Dúnedain of Cardolan died on the Barrow-downs, and evil spirits from Angmar and Rhudaur entered the realm.
The exact date the plague ended is not known but for the next two centuries Gondor, as well as its enemies, did little but try and regain strength. Historians believed that the Plague was caused by Sauron since the Shadow deepened in Mirkwood, foretelling his return in the (now unguarded) Mordor.