To answer the question as to whether pulmonary rehabilitation programs (PRP) induced increase in exercise tolerance (ET) is associated with increased levels of exhaled nitric oxide (eNO) in COPD patients of different degrees of severity, we designed a prospective and controlled study. Forty-seven stable COPD patients underwent an 8-week outpatient multidisciplinary PRP including supervised incremental exercise. Fractional eNO concentration (FE_NO) and peak work-rate (W_peak) were assessed baseline (T−1), at the end of 1-month run-in period (T 0), and after (T 1) the PRP. Lung function, walking test, health-related quality of life (HRQL) were also recorded. Patients were divided into three groups according to disease severity: 17 severe [FEV₁ 35 (5)% pred] COPD patients, seven of them with cor pulmonale; 15 mild [FEV₁ 78 (6)% pred], and 15 moderate [FEV₁ 56 (6)% pred] COPD patients. FE_NO did not differ at T -1 and T 0 (mean absolute change (SD): 0.03 (0.09) 95% Cl-0.01, 0.16, 0.06 (1.03) 95% Cl 0.03, 0.75 and 0.05 (0.06) 95% Cl 0.02, 0.11 ppb in mild, moderate and severe patients, respectively). As compared to T 0, both W_peak (by 17, 15 and 10%, respectively) and FE_NO (by 29, 24 and 16%, respectively) significantly increased in all groups, but not in patients with corpulmonale. A significant correlation between pre- and post-PRP changes in W_peak and FE_NO was found both in mild to moderate (r=0.79, P<0.00001) and severe (r=0.76, P<0.001) COPD patients. After a PRP, improvement in ET is associated with an increase in eNO also in most severe COPD patients, but not in those with cor pulmonale.