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STUDY OBJECTIVES: There are few studies evaluating (1) exercise capacity as assessed by the 6-minute walking distance (6MWD) test in large populations with obstructive sleep apnea (OSA); and (2) correlations with patients’ comorbidities. METHODS: This study presents a cluster analysis performed on the data of 1,228 patients. Severity of exercise limitation was defined on the basis of 6MWD. RESULTS: Sixty-one percent showed exercise limitation (29.2% and 31.9% mild and severe exercise limitation, respectively). About 60% and 40% of patients were included in cluster 1 (CL1) and 2 (CL2), respectively. CL1 included younger patients with high prevalence of apneas, desaturations, and hypertension with better exercise tolerance. CL2 included older patients, all with chronic obstructive pulmonary disease (COPD), high prevalence of chronic respiratory failure (CRF), fewer apneas but severe mean desaturation, daytime hypoxemia, more severe exercise limitation, and exercise-induced desaturations. Only CRF and COPD significantly (P < .001) correlated with 6MWD < 85% of predicted value. 6MWD correlated positively with apnea-hypopnea index, oxygen desaturation index, nocturnal pulse oxygen saturation (SpO(2)), resting arterial oxygen tension, mean SpO(2) on exercise, and negatively with age, body mass index, time spent during night with SpO(2) < 90%, mean nocturnal desaturation, arterial carbon dioxide tension, and number of comorbidities. Patients without severe comorbidities had higher exercise capacity than those with severe comorbidities, (P < .001). Exercise limitation was significantly worse in OSA severity class I when compared to other classes (P < .001). CONCLUSIONS: A large number of patients with OSA experience exercise limitation. Older age, comorbidities such as COPD and CRF, OSA severity class I, severe mean nocturnal desaturation, and daytime hypoxemia are associated with worse exercise tolerance. CITATION: Vitacca M, Paneroni M, Braghiroli A, et al. Exercise capacity and comorbidities in patients with obstructive sleep apnea. J Clin Sleep Med. 2020;16(4):531–538.