Rationale: Nocturnal hypoxemia and sympathetic/parasympathetic imbalance might contribute to the occurrence or atrial fibrillation (AF) in patients with obstructive sleep apnea (OSA). During sleep recordings, pulse rate variability (PRV) derived from oximetry might provide an accurate estimation of heart rate variability, which reflects the autonomic cardiovascular control. Objectives: We aimed to evaluate whether indices of oxygen desaturation and PRV derived from nocturnal oximetry were associated with AF incidence in patients investigated for OSA. Methods: Data from a large multicenter cohort of AF-free patients investigated for OSA between May 15, 2007, and December 31, 2017, were linked to health administrative data to identify hospitalized and nonhospitalized patients with new-onset AF. Cox proportional hazards models were used to evaluate the association between AF incidence and oximetry-derived indices automatically generated from sleep recordings. Results: After a median (interquartile range) follow-up of 5.34 (3.3-8.0) years, 181 of 7,205 patients developed AF (130 were hospitalized for AF). After adjusting for confounders, including anthropomorphic data, alcohol intake, cardiac, metabolic and respiratory diseases, beta blocker/calcium channel blocker medications, type of sleep study, study site, and positive airway pressure adherence, AF risk was associated with increasing nocturnal hypoxemia (P trend = 0.004 for quartiles of percentage of recording time with oxygen saturation <90%) and PRV (P trend < 0.0001 for quartiles of root mean square of the successive normal-normal beat interval differences), and decreasing sympathetic/parasympathetic tone (P trend = 0.0006 for quartiles of low-frequency power/high-frequency power ratio). The highest risk of AF was observed in patients with the highest quartiles of both the percentage of recording time with oxygen saturation <90% and the root mean square of the successive normal-normal beat interval differences compared with those with neither of these conditions (adjusted hazard ratio, 3.61; 95% confidence interval, 2.10-6.22). Similar associations were observed when the analyses were restricted to hospitalized AF. Conclusions: In patients investigated for OSA, nocturnal hypoxemia and PRV indices derived from single-channel pulse oximetry were independent predictors of AF incidence. Patients with both marked nocturnal hypoxemia and high PRV were at higher risk of AF. Oximetry may be used to identify patients with OSA at greatest risk of developing AF.