Eradicating screwworm, Cochliomyia hominivorax (Coquerel), from continental North American via the sterile insect technique has provided huge economic benefit to livestock producers by eliminating screwworm myiasis. After confirmatory identification of fly samples from infested deer by the USDA National Veterinary Services Laboratory on September 30, 2016, an alert was issued that screwworm myiasis was discovered in the Florida Keys. Personnel from USDA Animal and Plant Health Inspection Service, Agricultural Research Service, the State of Florida, U.S. Fish and Wildlife Service and local officials responded to the outbreak focus on Big Pine Key. After witnessing infested Key deer (Odocoileus virginianus clavium Barboyr & Allen), screwworm adult sampling was initiated at 0930 h on October 5, 2016 using nets to collect flies arriving at putrid liver, with the first female collected within 1 h. Larval samples were collected from infested animals for DNA analyses and to develop a “Florida outbreak” colony to test mating compatibility with the mass-produced strain used for sterile fly releases. Ground release chambers for sterile screwworm releases were placed in favorable habitats based on satellite image analyses. Sterile pupae were first placed in the chambers on October 11, 2016. Further liver trapping showed that 13 Keys were infested. One case, presumably through animal movement, occurred near Homestead on the Florida mainland. Ultimately there were 35 sterile fly release stations, including 4 located around Homestead, but no further cases were identified. About 188 million sterile flies were released until successful eradication was declared on March 23, 2017. Containing the outbreak prevented economic losses to livestock producers and other wildlife on the mainland and kept eradication costs to a minimum.