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At the Matlab Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh, the authors examined the blood groups of patients hospitalized between January and September 1979 for diarrheal disease due to a variety of bacterial and viral agents. A significant association was identified only for cholera, in which cholera patients were twice as likely to have blood group O and one-ninth as likely to have blood group AB as community controls. A follow-up study of family contacts of cholera patients, carried out between September 1980 and July 1982, indicated that blood group did not affect an individual's risk of having a culture-proven infection with V. cholerae 01 but was directly related to the severity of disease. Individuals with the most severe diarrhea compared with those with asymptomatic infection were more often of blood group O (68% versus 36%, p less than 0.01) and less often of AB (0% versus 7%, p less than 0.01). It was not possible to identify the molecular basis for this genetically related protection using biologic models of cholera that are currently available. The constant selective pressure of cholera against people of O blood group may account in part for the extremely low prevalence of O group genes and the high prevalence of B group genes found among the people living in the Gangetic Delta.