Impaired functional capacity is common in patients with mitral regurgitation (MR), but the determinants of functional capacity in patients with normal left ventricular (LV) function are unclear. Forty patients with chronic, isolated, nonrheumatic MR with no coronary artery disease underwent exercise echocardiography with continuous expired gas analysis. Cardiac output and regurgitant stroke volume were measured at rest and immediately after exercise by pulsed-wave Doppler echocardiography. For controls, 17 healthy volunteers without MR were also studied. Patients achieved a significantly lower VO2max compared with controls (25.6 +/- 7.7 vs 31.7 +/- 7.7 ml/kg/min, p = 0.008). VO2max showed better correlations with exercise cardiac output than with cardiac output at rest in both patients and controls. Multiple linear regression identified exercise cardiac output (partial r = 0.65), patient age (partial r = -0.56), and gender as independent determinants of VO2max (multiple R = 0.85, p <0.001). Cardiac output at rest, LV ejection fraction, regurgitant stroke volume, and fraction were not significant determinants. With exercise, the regurgitant stroke volume increased in 13 patients and decreased in 27 patients. The former 13 patients had a significantly lower exercise cardiac output (7.4 +/- 2.5 vs 9.4 +/- 2.6 L/min, p = 0.026). Patients who stopped exercise due to dyspnea (n = 7) had a significantly lower exercise cardiac output and VO2max compared with those who stopped due to fatigue (n = 33), with no differences in resting or exercise regurgitant volume. Patients with an increase in LV end-systolic volume with exercise (n = 8) also had a significantly lower exercise cardiac output (6.9 +/- 1.9 vs 9.2 +/- 2.7 L/min, p = 0.037) and showed a trend toward a lower VO2max (21 +/- 7.5 vs 26 +/- 6.4 ml/kg/min, p = 0.07). In patients with chronic MR, exercise cardiac output is the major determinant of VO2max. Regurgitant volume and fraction are not related to functional capacity. Limitations in functional capacity in these patients may be more related to a diminished cardiac reserve than to a large regurgitant volume.