Patients with chronic obstructive pulmonary disease (COPD) often lose weight during the course of their disease. We hypothesized that this may be due to skeletal muscle apoptosis. To investigate this possibility, we obtained quadriceps femoris biopsies in 15 patients with COPD (8 with normal body mass index [BMI] and 7 with low [< 20 kg/m²] BMI), 8 healthy volunteers, and 6 sedentary subjects undergoing orthopedic surgery (both groups with normal BMI). Skeletal muscle apoptosis was assessed by the transferase–mediated dUTP nick end labeling (TUNEL) technique and the immunodetection of poly-(ADP-ribose)-polymerase proteolytic fragments. Exercise tolerance on a cycloergometer was also determined in patients with COPD. We found that skeletal muscle apoptosis (by both techniques) was increased in patients with COPD and low BMI as compared with the other three groups (p < 0.005). In patients with COPD, BMI was inversely related to skeletal muscle apoptosis (TUNEL, p = 0.009), and it was better correlated with exercise capacity (p = 0.006) than with the degree of airflow obstruction present (p = 0.02). Markers of skeletal muscle apoptosis were not related to any of the measured lung function variables. This study shows that skeletal muscle apoptosis (1) is increased in patients with COPD having low BMI; and (2) is associated with a lower exercise tolerance despite a similar degree of lung function impairment.