Pulmonary diffusion capacity (D) for O2 and CO was determined from alveolar-mixed venous equilibration kinetics of 16O2, 18O2, and C18O measured during rebreathing by mass spectrometry. During the rebreathing maneuver (15 s) the ventilation was extremely high (about 100 1 X min-1) and PO2 and PCO2 in lung gas were close to their mixed venous values (aveolar hypoxia and hypercapnia). The following mean values (+/- SD) were found in six healthy males (20-33 yr) sitting on a bicycle ergometer (in ml X min-1 X Torr-1): 1) without work load, D18O2 = 54 +/- 10, Dc18O = 47 +/- 11; 2) with the highest work load tested (150 W, O2 uptake 2.1 l X min-1), D18O2 = 62 +/- 12, Dc18O = 54 +/- 8. The ratio D16O2/D18O2 averaged 1.07. The ratio D18O2/Dc18O, averaging 1.2 at rest and at all exercise levels, was close to the estimated O2/CO ratio of Krogh's diffusion constants for tissue and, therefore, was in agreement with the diffusion limitation model. An analysis of the various factors affecting the DO2/DCO ratio does not allow to reliably assess the role of diffusion in red blood cells and reaction with hemoglobin in limiting alveolar-capillary O2 transfer.