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<p><b>RATIONALE: </b>Sleep disorders may lead to stress-induced premature aging and telomere shortening.</p><p><b>OBJECTIVES: </b>To determine whether obstructive sleep apnea syndrome causing intermittent hypoxemic episodes was associated with telomere shortening independently from the comorbidities associated with this syndrome.</p><p><b>METHODS: </b>We conducted a cross-sectional study in 161prospectivelly enrolled, untreated, middle-aged men free of known comorbidities related or unrelated to sleep apnea. Each participant underwent full standard overnight polysomnography. Patients with apnea sleep syndrome were naive to treatment.</p><p><b>MEASUREMENTS AND MAIN RESULTS: </b>In univariate analysis, we found that telomere shortening was associated with older age, apnea-hypopnea index, oxygen desaturation index, waist circumference, and fat mass. After adjustment for age, only apnea-hypopnea index and oxygen desaturation index were significantly related to telomere shortening. The mean telomere length ratio was 0.70 ± 0.37 in the participants without sleep apnea, compared with 0.61 ± 0.22 and 0.53 ± 0.16 in those with mild to moderate and severe sleep apnea, respectively (P = 0.01). In multivariate analysis, we found that oxygen desaturation index was the only factor independently associated with telomere length. Arterial stiffness assessed by carotid-femoral pulse wave velocity correlated negatively with telomere length.</p><p><b>CONCLUSIONS: </b>Intermittent hypoxemia due to obstructive sleep apnea syndrome is a major contributor to telomere shortening in middle-aged men. Oxidative stress may explain this finding.</p>