Abstract Study Objectives To investigate the predictors of persistent driving risk related to sleepiness in patients with obstructive sleep apnea syndrome treated by continuous positive airway pressure. Methods Longitudinal analysis of a prospective national database including 5,308 patients with obstructive sleep apnea syndrome and an indication of continuous positive airway pressure. Near-misses related to sleepiness, accidents related to sleepiness, and sleepiness at the wheel were assessed before initiation and after ≥ 90 days of treatment. Multivariable associations with the cumulative incidence of near-misses and accidents under treatment were calculated using Cox models adjusted for age, sex, obesity, sleep duration, sleepiness at the wheel, accidents/near-misses history, depressive symptoms, residual apnea-hypopnea index, and adherence to treatment. Results Residual sleepiness at the wheel under treatment was associated with eight-fold higher incidence of near-misses related to sleepiness (HR=8.63 [6.08-12.2]) and five-fold higher incidence of accidents related to sleepiness (HR=5.24 [2.81-9.78]). Adherence ≤4h/night was also a significant predictor of persistent driving risk (HR=1.74 [1.12-2.71] for near-misses and HR=3.20 [1.37-7.49] for accidents). Conclusions Residual sleepiness at the wheel and treatment-adherence ≤4h/night are easy-to assess markers to detect persistent driving risk during the follow-up evaluations of patients under treatment. Health professionals, but also policy makers, should be aware of the crucial importance to systematically evaluate these elements during the follow-up evaluations of the patients with obstructive sleep apnea syndrome treated by continuous positive airway pressure to better evaluate their driving risk.