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The Setlik III massacre was a major event of the Federation-Cardassian War in which Cardassian forces attacked the Federation outpost on Setlik III and killed the majority of its inhabitants.

The Cardassian Union believed the outpost was a staging ground for an assault on Cardassian space, so a squad of the Cardassian militia was dispatched to the colony to destroy it. However, no such military base existed, and the Cardassian troops attacked the civilian population, with close to a hundred casualties. The Federation starship USS Rutledge, under the command of Captain Benjamin Maxwell, was the first vessel to respond to the colony's distress calls, though it was stationed some hours away. Upon arrival at Setlik III on the morning after the massacre, the Rutledge deployed landing parties, including tactical officer Miles O'Brien. O'Brien was instrumental in saving the last surviving colonists, who were all located in an outlying district of the settlement. As part of a squad to reinforce the survivors, O'Brien became known as the "Hero of Setlik III" and was decorated after leading a group of two dozen men against a Cardassian regiment at the Barrica encampment. Among O'Brien's other achievements on Setlik III was saving the lives of thirteen men by using a field transporter for the first time. (TNG: "The Wounded"; DS9: "Paradise", "Empok Nor")

Among the casualties were Maxwell's family, as well as Rutledge crewmembers Will Kayden and Raymond Boone. Boone himself was killed by the Cardassians after being captured. He was replaced by a surgically-altered Cardassian operative. He was not revealed as an impostor until 2370. (TNG: "The Wounded"; DS9: "Tribunal")

In 2367, Glinn Daro met O'Brien, and described the attack on Setlik III as "a terrible mistake", claiming that the Cardassians had erroneously believed it to have been the staging ground for a massive Federation attack. (TNG: "The Wounded")

The exact date of the massacre has never been stated. Miles O'Brien mentioned it to have taken place in 2347, about one year after he transferred to the USS Rutledge in 2346. (TNG: "The Wounded") Comments by Benjamin Sisko, on the other hand, seem to place the massacre shortly before the discharge of Raymond Boone from Starfleet "eight years ago" in 2362. (DS9: "Tribunal")
In the novelization of Emissary, O'Brien reflects on his memories of the massacre, and Captain Maxwell's discovery of his murdered family, while settling into his quarters aboard Deep Space 9, a former Cardassian space station.

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