To identify risk factors for Vibrio vulnificus infections, we performed a regional case-control study of 19 patients identified by isolates received at a state reference laboratory. Interviews with patients or surviving relatives and with three controls for each patient were compared in a matched analysis. Patients with V vulnificus wound infection were more likely than controls to have sustained a puncture wound while handling fresh seafood or to have been exposed to salt water. More patients with primary septicemia than controls had eaten raw oysters before the onset of illness. Other risk factors for septicemia included underlying liver disease, hematopoietic disorders, chronic renal insufficiency, use of immunosuppressive agents, and heavy alcohol consumption. Although V vulnificus infection is unusual, with a regional incidence of 0.8 per 100,000 population in this study, septicemia in the immunosuppressed patient is a devastating illness that can be prevented by not eating raw seafood.