OBJECTIVE To investigate the change of alveolar-arterial partial pressure of oxygen (PO2) difference [P (A-a) O2)] at rest and during exercise in patients with chronic obstructive pulmonary disease (COPD). METHODS Cardiopulmonary exercise testing was performed in 47 COPD male patients aged (66 +/- 8) at stable stage to measure the oxygen uptake (VO2) and carbon dioxide output (VCO2) continuously in a breath-by-breath mode. Arterial blood samples were drawn both at rest and during maximal exercise. P(A-a) O2 is computed by the equation: PAO2-PaO2. RESULTS The PaO2 level during exercise was (89 +/- 14) mm Hg, a little bit, however, not significantly, lower than that at rest [(92 +/- 9) mm Hg, P = 0.506]. The PaCO2 during exercise was 43 +/- 3 mm Hg, significantly higher than that at rest (41 +/- 4 mm Hg, P = 0.003). The patients were divided into two groups according to lung diffusing capacity for carbon monoxide (DLco). There was a significant increase in P(A-a) O2 from (16 +/- 8) mm Hg at rest to (42 +/- 9) mm Hg during maximal exercise in the DLco < 80% group (P = 0.005); however, in the DLco >80% group the P(A-a) O2 level during maximal exercise was (26 +/- 6) mm Hg, not significantly different from that at rest [(20 +/- 6) mm Hg, P = 0.106]. The P(A-a)O2 level of the DLco <80% group during maximal exercise was (42 +/- 9) mm Hg, significantly higher than that at rest [(16 +/- 8) mm Hg, P = 0.005]. The P(A-a)O2 was significantly negatively correlated with the forced vital capacity (r= -0.581, P = 0.037) and DLco (r = -0.671, P = 0.012). CONCLUSIONS The increase in P (A-a) O2 during exercise in the COPD patients is mainly due to the limited diffusing capacity of the lung.