Objectives This study sought to evaluate mechanisms of effort intolerance in patients with rheumatic mitral stenosis (MS). Background Combined stress echocardiography and cardiopulmonary testing allows assessment of cardiac function, hemodynamics, and oxygen extraction (A–Vo2 difference). Methods Using semirecumbent bicycle exercise, 20 patients with rheumatic MS (valve area 1.36 ± 0.4 cm2) were compared to 20 control subjects at 4 pre-defined activity stages (rest, unloaded, anaerobic threshold, and peak). Various echocardiographic parameters (left ventricular volumes, ejection fraction, stroke volume, mitral valve gradient, mitral valve area, tissue s′ and e′) and ventilatory parameters (peak oxygen consumption [Vo2] and A–Vo2 difference) were measured during 8 to 12 min of graded exercise. Results Comparing patients with MS to control subjects, significant differences (both between groups and for group by time interaction) were seen in multiple parameters (heart rate, stroke volume, end-diastolic volume, ejection fraction, s′, e′, Vo2, and tidal volume). Exercise responses were all attenuated compared to control subjects. Comparing patients with MS and poor exercise tolerance ( Conclusions In patients with rheumatic MS, exercise intolerance is predominantly the result of restrictive lung function, chronotropic incompetence, limited stroke volume reserve, and peripheral factors, and not simply impaired valvular function. Combined stress echocardiography and cardiopulmonary testing can be helpful in determining mechanisms of exercise intolerance in patients with MS.