Partial sleep deprivation (PSD) results in a pronounced decrease of depressive symptoms in the majority of patients with major depressive disorder. Generally this acute antidepressant effect is not stable, relapse usually occurs after one night of recovery sleep. We therefore studied whether light therapy, beginning in the morning after PSD, is able to prevent the relapse after sleep deprivation, using a controlled, balanced, parallel design. All patients received an antidepressant medication, which was kept constant before and during the study period. Fourteen of 20 patients (70%) showed a reduction of at least 40% in the Hamilton Depression Rating Scale (HDRS) in the morning after PSD and were classified as PSD responders. Responders as well as nonresponders were randomly assigned to receive either bright light (BL/3000 lux) or dim light (DL/100 lux) therapy during the following 6 days after PSD. In the responder group BL therapy prevented significantly (p = 0.005) the relapse after the next night of sleep and prolonged significantly (p = 0.011) the antidepressant effects of PSD up to 7 days. In contrast, patients in the DL condition relapsed after the recovery night and showed no further improvement of the depressive syndrome after 1 week of DL therapy. PSD nonresponders did not benefit from light treatment. These findings indicate that BL therapy might be efficacious to prevent relapse after PSD.