To delineate possible genetic factors involved in the pathogenesis of childhood duodenal ulcer (DU), serum pepsinogen I concentrations were measured in 14 patients and their parents. Sixty-five normal subjects were simultaneously studied to determine normal values in relation to age. Hyperpepsinogenemia occurred in six of 14 patients and 13 of 28 parents. Hyperpepsinogenemic patients invariably had hyperpepsinogenemic parents, four of six having both parents affected. Hyperpepsinogenemic parents (10 of 13) usually but not invariably gave birth to hyperpepsinogenemic patients. Most hyperpepsinogenemic parents (11 of 13) were asymptomatic. Our findings suggest a genetic basis (hyperpepsinogenemia) for the predisposition to childhood DU in nearly half the patient population, the inheritance being likely to be autosomal dominant with incomplete penetrance. In addition, the existence of normopepsinogenemic families suggests that childhood DU is a heterogeneous entity and not a single disease. A high familial incidence of DU is also present in the normopepsinogenemic subgroup (four of eight) but whether genetic factors or socioenvironmental factors are responsible here will require elucidation from studies with other markers.