We describe a patient with non-O1, non-O139 Vibrio cholerae septicemia associated with hemorrhagic bullous skin lesions of the lower extremities. The patient had underlying liver disease, and he probably acquired the organism through ingestion of raw clams. Although his condition rapidly improved during appropriate therapy, the patient's cellulitis and skin lesions persisted and he developed a fluid collection of the lower extremity that required drainage. Molecular methods were used to examine the non-O1 V. cholerae isolate for several known virulence factors of V. cholerae O1. The isolate failed to express cholera toxin and toxin-coregulated pilus (Tcp) and was negative in Southern hybridizations for ctxB, tcpA, toxR, and toxT. The vast majority of vibrio infections in the United States are clustered in the Gulf Coast area. This patient acquired the infection on Cape Cod. To our knowledge, this is the first case of non-O1 V. cholerae septicemia reported to have occurred in Massachusetts. Given the high fatality rate of this infection, it is important for physicians to consider this diagnosis in patients who have underlying risk factors and appropriate epidemiologic exposures, even when they reside as far north as the New England states.