The natural history of patients with severe nonischemic mitral regurgitation (MR) from mitral valve prolapse, who are asymptomatic or minimally symptomatic and have normal right ventricular (RV) and left ventricular (LV) performance, has not been evaluated previously. To define natural history in this population and to determine if any objective variables could predict disease progression, 31 patients were followed annually with severe MR due to prolapse, who at entry were asymptomatic or minimally symptomatic and had normal RV and LV performance at rest by radionuclide cineangiography. Average follow-up in patients not reaching surgical end point was 4.7 years. The Kaplan-Meier product limit estimates were used to determine the rate of progression to either "operable" symptoms or to previously defined "high risk" ventricular performance descriptors, if the latter occurred first. Univariate comparisons of Kaplan-Meier curves and multivariate Cox proportional hazards analyses were used to define prognostically important variables measured at entry. Fourteen patients developed symptoms warranting referral for operation; none developed high-risk ventricular performance descriptors. The annual end point risk was 10.3%. Of all covariates, only change in RV ejection fraction from rest to exercise was significantly associated with disease progression. Annual risk of progression to surgical end point was 4.9% in the subgroup in which this parameter increased with exercise and 14.7% in the subgroup without an increase (p = 0.04). Patients with severe MR due to mitral valve prolapse, who are asymptomatic or minimally symptomatic with normal ventricular performance, can be expected to progress to surgical indications at an annual rate of 10.3%.(ABSTRACT TRUNCATED AT 250 WORDS)