Objective: To evaluate the efficacy and safty of modafinil for residual sleepiness(RS) in patients with obstructive sleep apnea syndrome (OSAS) treated by continuous positive airway pressure (CPAP). Methods: Thirty-two male patients with mild-to-moderate OSAS under CPAP treatment were selected. All of them had Epworth seepiness scale(ESS)>10. The study included three stages (T1,T2 and T3). Following baseline evaluation (T1),patients were randomly allocated to the modafinil or placebo group. The second stage(T2): all subjects were instructed to take a piece of modafinil or placebo (100 mg) for 7 days. The third stage (T3): patients were instructed to take two pieces of modafinil or placebo(200 mg) for 28 days. Patients underwent a final evaluation on the last day of the third stage. The evaluations at T1 and T3 consisted of routine blood, blood biochemical tests, routine urine, electrocardiogram, nocturnal polysomnography (PSG) and multiple sleep latency test (MSLT). In addition, ESS was constantly detected during T1, T2 and T3 . Results:Before and after treatment, there were no significant changes both in Apnea Hyponea Index (AHI) and the per-night use time of CPAP between the modafinil and placebo groups. After treatment, comparing with the placebo group,the mean sleep leatency was lengthened and ESS score was decreased in the modafinil group,and both differences had statistical significance (P < 0.05). In addition,in the modafinil group,changes of ESS was significantly greater in T3 with 200 mg than that in T2 with 100 mg (F=0.719,P=0.015). Adverse drug reactions occurred in 62.5% patients in the modafinil group, such as dry mouth, nausea,headache and so on. there was no significant difference between the reactions (P=0.41),and all of these adverse drug reactions were mild to moderate in severity. Conclusion: Modafinil was effective and well tolerated for improving RS in OSAS patients under CPAP treatment.