A transient form of hypertrophic cardiomyopathy has been previously described in infants of diabetic mothers (IDMs). The purpose of this study was to determine the incidence, natural history and pathologic features of this cardiomyopathy in symptomatic and asymptomatic IDMs. We studied 47 IDMs for evidence of cardiomyopathy. Among 24 symptomatic IDMs, five had marked septal hypertrophy with echocardiographic features suggesting left ventricular outflow obstruction and five had hypertrophy of the right ventricular free wall. With the exception of mild septal hypertrophy, these abnormalities resolved during the first 6 months of life, and echocardiograms in the first-degree family members were normal. Of 23 asymptomatic IDMs, three had septal hypertrophy and two had right ventricular free wall hypertrophy; none of the asymptomatic IDMs had evidence of outflow obstruction. One symptomatic IDM died, and autopsy revealed a hypertrophic septum that distorted both ventricular cavities. Microscopic examination revealed hypertrophic fibers and occasional areas of cellular disarray in the septum. Despite the clinical and pathologic similarities of the cardiomyopathy in IDMs to the hypertropic cardiomyopathies in older children and adults, its transient and nonfamilial nature suggest that it is a separate disease. We speculate that it is a manifestation of the generalized organomegaly in IDMs.