Early lactic acidosis has been suggested as negatively influencing the exercise capacity of patients with chronic obstructive pulmonary disease (COPD). We conducted a study to investigate whether the early lactate (La) response to exercise in COPD is related to alterations in exercise-related substrate levels in resting muscle, associated with physical inactivity. Twenty-seven COPD patients and 22 controls (physically inactive [PI] subjects, n = 15; and physically active [PA] subjects, n = 7) performed an incremental cycle test. Venous blood was sampled for La analyses, and the oxygen uptake at which the La level began to rise (La threshold) was calculated. Vastus lateralis biopsy specimens were obtained at rest. In the PA group, muscle glutamate (GLU) and glycogen were higher, but muscle La, pyruvate, and glucose were not different than in the PI group. Moreover, the La threshold was higher in the PA group. The COPD group had lower values for La threshold and muscle GLU, and higher values for muscle La and pyruvate levels than did the PI group. Stratification of patients into those with and without macroscopic emphysema (EMPH+, EMPH-, respectively), with comparable physical activity levels on the basis of previous observations, revealed lower values for La threshold and GLU in EMPH+ patients. Diffusing capacity for carbon monoxide (DL(CO)) and arterial oxygen tension (Pa(O(2))) in the four study groups were positively related to GLU and La threshold. Moreover, La threshold was positively related to GLU. This study illustrates that the early lactic acidosis during exercise in patients with COPD is associated with the physical inactivity-related reduction in these patient's muscle GLU. However, factors other than physical inactivity, such as Pa(O(2)) or DL(CO), play a role in the different La responses during exercise in subjects with different subtypes of COPD.