Already in an early disease stage, patients with chronic obstructive pulmonary disease (COPD) are confronted with impaired skeletal muscle function and physical performance due to a loss of oxidative type I muscle fibers and oxidative capacity (i.e. oxidative phenotype; Oxphen). Physical activity is a well-known stimulus of muscle Oxphen and crucial for its maintenance. We hypothesized that a blunted response of Oxphen genes to an acute bout of exercise could contribute to decreased Oxphen in COPD. For this28 patients with less advanced COPD (age 6567 yrs, FEV1 59616% predicted) and 15 age- and gender-matched healthy controls performed an incremental cycle ergometry test. The Oxphen response to exercise was determined by the measurement of gene expression levels of Oxphen markers in pre and 4h-post exercise quadriceps biopsies. Because exercise-induced hypoxia and oxidative stress may interfere with Oxphen response, oxygen saturation and oxidative stress markers were assessed as well. Regardless of oxygen desaturation and absolute exercise intensities, the Oxphen regulatory response to exercise was comparable between COPD patients and controls with no evidence of increased oxidative stress. In conclusion, the muscle Oxphen regulatory response to acute exercise is not blunted in less advanced COPD, regardless of exercise-induced hypoxia. Hence, this study provides further rationale for incorporation of exercise training as integrated part of disease management to prevent or slow down loss of muscle Oxphen and related functional impairment in COPD. © 2014 Slot et al.