El Dorado was a great treasure, hidden in a remote Amazon temple. It was found by the Spanish approximately 400 years before the events of Drake's Fortune. They moved it to an uncharted island in the middle of the Pacific Ocean on a ship named the Esperanza, and built a large colony around it. They hid the treasure in an extremely elaborate labyrinth beneath the island. It was later moved into a network of catacombs underneath the island's monastery by the Germans at some point during the early to mid twentieth century. Nathan Drake and Victor Sullivan track down its location, along with Atoq Navarro and Gabriel Roman. Upon opening the sarcophagus, Roman is infected with a virus that causes him to become feral. He is shot dead by Navarro, who airlifts the sarcophagus to his boat. After a brief fight, Nathan Drake manages to knock the treasure into the Pacific Ocean, where it sinks into the deep.
The mummified body inside the sarcophagus carries an extremely detrimental, ancient and unidentified virus, which is dispersed through the air. It immediately affects victims, causing them to become extremely violent. As the virus is extremely rare, nobody who encounters it has any innate or acquired immunity to it. It's effects become progressively worse over time, and can be seen affecting both Gabriel Roman and a German soldier in a brief piece of film footage that Nate views in the submarine bunker. The Spanish colonists were similarly infected, and through centuries of inbreeding, evolved into mutant creatures that became known as the Descendants.
- It is a popular misconception that the statue carries a "curse." Naughty Dog co-president Evan Wells addressed the issue by saying, "there are mystical elements to the world that don't necessarily have a supernatural explanation...the idea was that there was this virus trapped inside that sarcophagus...and it has some really nasty effects."
- The idol in Plunder (Uncharted 2: Among Thieves Multiplayer Gamemode) resembles a miniature El Dorado.
- In Nepal, there are signs in the street saying "Hotel El Dorado".
- Nate and Sully in the beginning of the game first thought that El Dorado was a "lost city of gold".
- In the game PlayStation All-Stars Battle Royale, Nate's Level 3 Special releases El Dorado's Virus, triggering an effect where his enemies turn into Descendants, making them slow, easy targets, as they are picked off by Nate with one shot.