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Chronic obstructive pulmonary disease (COPD) and atrial fibrillation (AF) are characterized by increased oxidative stress, but the impact of the coexistence of COPD and AF on systemic oxidative stress is unclear. We performed a cross-sectional study including 157 outpatients to investigate the Nox2-related oxidative stress in patients with AF and COPD. COPD was defined by an FEV 1 /FVC <0.70. Oxidative stress was measured by sNox2-dp, a marker of Nox2 activation, and urinary isoprostanes. We divided patients into four groups: Group 0: hypertension ( n  = 49, controls); Group 1: COPD ( n  = 42); Group 2: AF ( n  = 33); and Group 3: COPD and AF ( n  = 33). Mean age was 68.3 ± 11.0 years, and 46.5% were women. Patients with COPD or AF showed increased levels of sNox2-dp as compared with group 0; sNox2-dp further increased in patients with COPD + AF. In these patients, sNox2-dp was higher than in those with COPD ( p  < 0.001) or AF ( p  = 0.003). At multivariable logistic regression analysis, chronic kidney disease, COPD, and AF were associated with sNox2-dp above median. Similar results were observed for urinary isoprostanes. We hypothesize that the coexistence of COPD in AF patients may be associated with an increased systemic oxidative stress by the upregulation of Nox2. Antioxid. Redox Signal. 31, 786-790.