The volume dependence of single breath carbon monoxide diffusing capacity (DLCO) and carbon monoxide transfer coefficient (KCO) was determined in 24 healthy subjects. The change in DLCO [fraction of DLCO measured at total lung capacity (TLC)] to change in alveolar volume [fraction of alveolar volume (VA) at TLC] closely fitted a simple linear regression and matched a theoretical model. As VA decreased, DLCO fell linearly and KCO increased as expected from the relation of DLCO to VA. The equations for adjustment of predicted DLCO and KCO for alveolar volume are: DLCO/DL COtlc = 0.58 + 0.42 VA/VAtlc, KCO/KCOtlc = 0.42 + 0.58/(VA/VAtlc). DLCO and KCO were evaluated in 2313 patients. Subgroups of patients with asthma, emphysema, extrapulmonary lung disease, interstitial lung disease and lung resection were identified. Unadjusted DLCO and KCO percent predicted values showed large differences and much variability, so can be misleading. As expected, KCO and DLCO percent predicted values adjusted for alveolar volume were nearly identical. Subgroups have characteristic patterns of VA and unadjusted and adjusted DLCO and KCO. Changes in DLCO and KCO with alveolar volume are relevant for accurate interpretation of diffusion in patients with low lung volumes. Adjusting predicted DLCO and KCO for alveolar volume provides a better assessment of lung function.