In July 2015, personnel in the Alaska Division of Public Health's Section of Epidemiology became aware of an increase in the number of patients being treated in Anchorage hospital emergency departments for adverse reactions associated with use of synthetic cannabinoids (SCs). SCs are a chemically diverse class of designer drugs that bind to the same cannabinoid receptors as tetrahydrocannabinol, the main psychoactive component of cannabis. A public health investigation was initiated to describe clinical outcomes, characterize the outbreak, and identify SC chemicals circulating in Anchorage. During July 15, 2015-March 15, 2016, a total of 1,351 ambulance transports to Anchorage emergency departments for adverse SC reactions were identified. A review of charts obtained from two Anchorage hospitals determined that among 167 emergency department visits for adverse SC reactions during July 15-September 30, 2015, 11 (6.6%) involved a patient who required endotracheal intubation, 17 (10.2%) involved a patient who was admitted to the intensive care unit, and 66 (39.5%) involved a patient classified as being homeless. Testing of 25 product and paraphernalia samples collected from patients at one hospital identified 11 different SC chemicals. Educational outreach campaigns focused on the considerable health risks of using SCs need to complement judicial and law enforcement actions to reduce SC use.