Recent studies have suggested that Plesiomonas shigelloides is a cause of diarrhea. The present study addresses the clinical features, epidemiology, and response to antimicrobial therapy of P. shigelloides diarrhea. Thirty cases of P. shigelloides infection were defined by isolation of the organism from stool specimens, and 30 age-matched control patients were identified by detection of other enteric pathogens. Clinical and epidemiological information was obtained by interviewing the referring physicians and the patients. Of the P. shigelloides-infected patients, 71% had a history of recent tropical travel, but 29% acquired their infections locally in association with the consumption of seafood or untreated water or both. Seventy-eight percent of the P. shigelloides-infected patients had findings suggestive of colitis, and P. shigelloides-infected patients had a history of tropical travel, acute illness, abdominal pain, and prolonged symptoms significantly more often than did the control patients. Antimicrobial therapy significantly reduced the duration of illness in patients with Plesiomonas diarrhea. These results suggest that P. shigelloides is a significant cause of both locally acquired and traveler's diarrhea that may respond to antimicrobial therapy.