Background As a treatment of depression, the efficacy of conventional repetitive transcranial magnetic stimulation (rTMS) is limited, and symptoms recurrence is easy to occur after the treatment. This study aimed to examine the efficacy and safety of sleep electroencephalogram modulated repetitive rTMS (SEM-rTMS) in the treatment of depression.Methods After 7 days without psychoactive medication, 164 patients with clinically defined depression were randomly divided into 3 groups: SEM-rTMS group (n=57), conventional rTMS (C-rTMS, n=55) group and sham-rTMS group (n=S2). Every patient was treated with the corresponding method for 30 minutes everyday for 10 days. Before and after scores on the 24-item Hamilton rating scale for depression (HAMD-24) and the clinical outcome on the 10th day of therapy for all subjects were analyzed.Results Twenty-two cases in the SEM-rTMS group obtained improved mood as compared to 6 in the C-rTMS group and 2 in the sham-rTMS group (X2=15.89, P=0.0004). After completion of the rTMS phase of the protocol, a (51±5)% reduction of HAMD-24 scores from the baseline in the SEM-rTMS group was found compared with a (34±4)% in the C-rTMS group (g=26.09, P=0.001) and a (14±3)% in sham-rTMS group (q=57.53, P=0.000). The 88% total effective rate in the SEM-rTMS group was significantly higher than 68% in the C-rTMS group and 20% in the sham-rTMS group (X2=12.01, P=0.0025). No significant side effects were noted.Conclusion SEM-rTMS is an effective and safe way for treating depression with repetitive transcranial magnetic stimulation (ChiCTR-TRC-00000438).