To test whether orthotopic heart transplant (OHT) patients with low pulmonary diffusion capacity have a greater limitation to exercise than OHT patients with normal pulmonary diffusion capacity, we investigated cardiorespiratory responses and blood gases in two groups of OHT patients, one with low (LdG) and the other with normal pulmonary diffusion capacity (NdG), during a graded exercise test. The results showed 1) significantly reduced peak power (P < 0.05), peak oxygen uptake (˙VO2,P < 0.001), peak oxygen pulse (˙VO2/heart rate,P < 0.01), peak minute ventilation (˙VE, P < 0.05), and delta PaO2 (peak PaO2 - rest PaO2,P< 0.05) in LdG versus NdG; 2) a nonsignificant decrease in peak heart rate in LdG (P < 0.13, β = 24%); and 3) significant increases in peak respiratory equivalent for oxygen (˙VE/˙VO2, P< 0.05) and delta P(A-a)O2 (peak P(A-a)O2 - resting P(A-a)O2, P < 0.05) in LdG versus NdG. No significant difference was found for PaO2 and PaCO2 at rest or at peak exercise between the groups. A strong correlation was found between pulmonary diffusion capacity (TLCO/VA) and peak ˙VO2 (r = 0.81, P< 0.01); that is, TLCO/VA explains 66% of the variance in peak˙VO2. We conclude that OHT patients with decreased pulmonary diffusion capacity have a lower exercise tolerance than patients with normal pulmonary diffusion capacity. However, because of the lack of exercise-induced hypoxemia, diffusion abnormalities are not the main limiting factor for exercise tolerance in the low diffusion group.