Wasted ventilation fraction (Vd/Vt) normally declines substantially during exercise in persons without lung disease. Failure of Vd/Vt to decrease during exercise has been reported to be one of the earliest abnormalities in patients with dyspnea caused by pulmonary vaso-occlusive disease, suggesting that measurement of Vd/Vt at rest and during exercise are useful in the diagnosis of pulmonary vascular disorders. We studied pulmonary hemodynamic and Vd/Vt responses to exercise in 11 patients in the supine position with suspected pulmonary vascular involvement caused by progressive systemic sclerosis, systemic lupus erythematosus, or recurrent pulmonary emboli, 10 of whom had dyspnea at rest and/or on exertion. In contrast to previous reports of no change or an increase in Vd/Vt during exercise in patients with pulmonary vascular disease, we found Vd/Vt to decrease significantly during exercise in 8 of 9 patients in whom mean pulmonary artery pressures were abnormally elevated at rest and/or during exercise. Our findings suggest that normal responses of Vd/Vt to exercise do not exclude hemodynamically significant pulmonary vaso-occlusive disease.