We have examined the effect of chronic airways obstruction on the measurement of the single-breath carbon-monoxide-diffusing capacity (DLCLSB). We reviewed the results of 136 consecutive pulmonary function tests (comprising standard spirometry, helium dilution lung volumes and DLCOSB) obtained in patients who had an FEV1/FVC less than 70%. We calculated DLCOSB using two different values for alveolar volume (VA). In the first method (HeDL), VA was measured by single-breath dilution of helium during the test. In the second method (RbDL), VA was measured as the sum of the inspiratory vital capacity, performed during the test, and the residual volume, determined separately by helium rebreathing. The mean HeDL/RbDL, reflecting disparity between computations of DLCOSB in individual subjects was 0.85 +/- 0.13 in patients with moderate obstruction (40 less than or equal to FEV1/FVC% less than 60) and was 0.80 +/- 0.14 in those with severe obstruction (FEV1/FVC% less than 40). The mean HeDL/RbDL was lowest (0.73 +/- 0.12) in those with severe elevation of RV/TLC (RV/TLC% greater than 60). HeDL/RbDL correlated best with RV/TLC (r = -0.71, p less than 0.001). Unexplained variance in HeDL/RbDL was not significantly reduced by including the relationship between HeDL/RbDL and pulmonary function indices commonly used to measure airways resistance. These data suggest (1) the difference between HeDL and RbDL in patients with moderate and severe chronic airways obstruction is greater than previously reported; (2) the disparity between HeDL and RbDL stems from slow space ventilation rather than from increased resistance to air flow, and (3) HeDL underestimates gas transfer in poorly ventilated lung compartments.