Although mitral regurgitation and fibromyxomatous thickening of the mitral leaflets have long been recognized as such, mitral valve prolapse has only recently been added as one of the pleiotropic features of the Marfan syndrome. The prevalence, age of onset, and natural history of mitral valve dysfunction in this condition are uncertain. Therefore, all patients in one clinic who met strict diagnostic criteria for the Marfan syndrome and who had clinical and echocardiographic examinations before age 22 years were reviewed. Of the 166 patients (84 males, aged 11.9 +/- 0.6 years [mean +/- SEM]; and 82 females, 11.0 +/- 0.6 years), 52 percent had auscultatory and 68 percent had echocardiographic evidence of mitral valve dysfunction, generally mitral valve prolapse. Prevalence did not differ between the sexes. Follow-up in 115 patients averaged five examinations over a mean of four years; 17 percent were followed for more than six years. Criteria for progression of mitral valve dysfunction were: (1) on auscultation, the appearance of new systolic clicks or apical systolic murmurs, a mitral regurgitant murmur increased by two grades, or appearance of congestive heart failure not due to aortic regurgitation; and (2) on echocardiography, the new appearance of mitral valve prolapse or abnormally increased left atrial dimension. Nearly half the patients met at least one criterion and one quarter had both auscultatory and echocardiographic evidence of progressive mitral valve dysfunction. Twice as many females demonstrated worse mitral valve function with time. Eight of the 166 patients either died as a result of mitral valve dysfunction or required mitral valve replacement. Severe mitral regurgitation developed in an additional 15 patients. Rupture of chordae tendineae was uncommon. Antibiotic prophylaxis was routine, and no cases of bacterial endocarditis of the mitral valve occurred. These results suggest that mitral valve dysfunction is extremely common in young patients with Marfan syndrome and usually presents as mitral valve prolapse. Serious mitral regurgitation develops in one of every eight patients by the third decade. Thus, the prevalence and natural history of mitral valve prolapse in the Marfan syndrome appear distinct from mitral valve prolapse associated with other conditions, including idiopathic or familial mitral valve prolapse.