Background: Hypersomnia is a cardinal symptom of seasonal affective disorder/winter depression. This open-label pilot study assessed modafinil, a novel wake-promoting agent, as treatment for seasonal affective disorder/winter depression. Methods: Total daily modafinil dose was 100 mg (all patients week 1), and 100 mg or 200 mg split dose (weeks 2–8). Efficacy assessments (weeks 1, 2, 5, and 8) included the Structured Interview Guide for the Hamilton Depression (HAM-D) Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD), Montgomery–Asberg Depression Rating Scale (MADRS), Clinical Global Impression of Change (CGI-C), Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS). Results: Thirteen patients (11 women; mean age, 41 years) were enrolled, 12 were evaluable for efficacy (100 mg dose, five patients; 200 mg dose, seven patients), and nine completed treatment. Modafinil significantly improved winter depression as shown by reductions from baseline in mean SIGH-SAD at week 1 (P<0.01) through week 8 (P<0.001 weeks 2–8) and MADRS total scores from week 2 through week 8 (P<0.01 for all). At week 8, mean SIGH-SAD total score was 17.1 (versus 37.2 at baseline, P<0.001), and mean MADRS total score was 13.3 (versus 26.9 at baseline, P<0.01). Modafinil significantly improved overall clinical condition at all time points (P<0.001). The response rate was 67% on the SIGH-SAD (29 item), HAM-D (21 item), and MADRS, and 100% on eight atypical SIGH-SAD items. Modafinil significantly reduced fatigue (FSS) and improved wakefulness (ESS) from weeks 2 through 8 (P<0.01). Modafinil was well tolerated. Limitations: This was an open-label, single site study. Conclusions: Modafinil may be an effective and well-tolerated treatment in patients with seasonal affective disorder/winter depression.