Increased prevalence of illicitly manufactured fentanyl and fentanyl analogs has contributed substantially to overdose deaths in the United States (1-3). On October 26, 2015, CDC issued a Health Advisory regarding rapid increases in deaths involving fentanyl. This CDC Health Advisory has been updated twice to address increases in fentanyl and fentanyl analog overdoses and their co-occurrence with nonopioids (4). Deaths involving carfentanil, an analog reportedly 10,000 times more potent than morphine and 100 times more potent than fentanyl, were first reported in Florida, Michigan, and Ohio in 2016 and described in an August 2016 CDC Health Advisory (1,5). Carfentanil is used to rapidly immobilize large animals in veterinary medicine and has no U.S. approved therapeutic use in humans. Carfentanil's street price per dose is likely lower than that of heroin. During 2016 and 2017, an outbreak of carfentanil-involved fatal overdoses in Florida emerged, and the Medical Examiner jurisdiction serving Sarasota, Manatee, and DeSoto counties (the Sarasota area) was the outbreak epicenter. This report describes toxicology profiles, sociodemographic information, and geographic distributions of carfentanil-involved fatal overdoses (carfentanil deaths) in the Sarasota area compared with those in the rest of Florida (i.e., all Florida counties excluding Sarasota area) from January 2016 to December 2017. The Sarasota area accounted for 19.0% of 1,181 statewide carfentanil deaths that occurred during this time and experienced a peak in carfentanil deaths preceding the larger Florida outbreak. The report of a single carfentanil death from August to December 2017 (compared with 73 reported deaths during the same period in 2016) appeared to mark the end of the outbreak in the area. The threat of such rapid, intense fatal overdose outbreaks highlights the need for accelerated reporting, reliable data sharing systems, and novel proactive surveillance to support targeted prevention and response efforts by public health and safety organizations (6).