On April 2, 2015, four patients were evaluated at the University of Mississippi Medical Center (UMMC) in Jackson, Mississippi, for agitated delirium after using synthetic cannabinoids. Over the next 3 days, 24 additional persons went to UMMC with illnesses suspected to be related to synthetic cannabinoid use; one patient died. UMMC notified the Mississippi State Department of Health, which issued a statewide alert via the Health Alert Network on April 5, requesting that health care providers report suspected cases of synthetic cannabinoid intoxication to the Mississippi Poison Control Center (MPCC). A suspected case was defined as the occurrence of at least two of the following symptoms: sweating, severe agitation, or psychosis in a person with known or suspected synthetic cannabinoid use. A second statewide alert was issued on April 13, instructing all Mississippi emergency departments to submit line lists of suspected patients to MPCC each day. By April 21, 16 days after the first alert was issued, MPCC had received reports of approximately 400 cases, including eight deaths possibly linked to synthetic cannabinoid use; in contrast, during April 2012–March 2015, the median number of telephone calls to MPCC regarding synthetic cannabinoid use was one per month (range = 0–11). The Mississippi State Department of Health, with the assistance of CDC, initiated an investigation to better characterize the outbreak, identify risk factors associated with severe illness, and prevent additional illnesses and deaths.