In the present study, we have undertaken a detailed analysis of the respiratory physiologic correlates of SaO2 during mild constant-load exercise in 38 patients with severe but stable COPD. Several respiratory physiologic variables that would be expected to influence exercise SaO2 were entered into a stepwise multiple linear regression analysis with mean exercise SaO2 as the dependent variable. Two variables (Dco and resting SaO2) were found to correlate strongly with mean exercise SaO2 (multiple r = 0.80; p less than 0.00001) and accounted for 65 percent of the variability among patients. The PaCO2 influenced resting SaO2 but had no independent influence on exercise SaO2. Subsequently, the model of mean exercise SaO2 derived in the present analysis was found to accurately predict mean exercise SaO2 in a group of 19 similar patients (r = 0.85; p less than 0.0001). While these findings do not establish a cause-and-effect relationship, they may provide clinicians with further insight as to which patients are likely to desaturate during exercise.