Background Low-field magnetic stimulation (LFMS) has mood-elevating effect, and the increase of brain-derived neurotrophic factor (BDNF) is associated with antidepressant treatment. We evaluated the effects and association with BDNF of rhythmic LFMS in the treatment of major depressive disorder (MDD).Methods A total of 22 MDD patients were randomized to rhythmic alpha stimulation (RAS) or rhythmic delta stimulation (RDS), with 5 sessions per week, lasting for 6 weeks. Outcomes assessments included the 17-item Hamilton Depression Rating Scale (HAMD-17), the Hamilton Anxiety Rating Scale (HAMA), and the Clinical Global Impressions-Severity scale (CGI-S) at baseline and at weeks 1, 2, 3, 4, and 6. Serum BDNF level was measured at baseline and at weeks 2, 4, and 6.Results HAMD-17, HAMA, and CGI-S scores were significantly reduced with both RAS and RDS. RAS patients had numerically greater reductions in HAMD-17 scores than RDS patients (8.9 and plusmn; 7.4 vs. 6.2 and plusmn; 6.2, effect size [ES]=0.40), while RDS patients had greater improvement in HAMA scores (8.2 and plusmn; 8.0 vs. 5.3 and plusmn; 5.8, ES=0.42). RAS was associated with clinically relevant advantages in response (54.5% vs. 18.2%, number-needed-to-treat [NNT]=3) and remission (36.4% vs. 9.1%, NNT=4). BDNF increased significantly during the 6-week study period (p and lt;0.05), with greater increases in RAS at weeks 4 and 6 (ES=0.66 - 0.76) and statistical superiority at week 2 (p=0.034, ES=1.23). Baseline BDNF in the 8 responders (24.8 and plusmn;9.0 ng/ml) was lower than in the 14 nonresponders (31.1 and plusmn;7.3 ng/ml, p=0.083, ES=-0.79), and BDNF increased more in responders (8.9 and plusmn;7.8 ng/ml) than in nonresponders (1.8 and plusmn;3.5 ng/ml, p=0.044). The change in BDNF at week 2 was the most strongly predicted response (p=0.016).Conclusions Rhythmic LFMS was effective for MDD. BDNF may moderate/mediate the efficacy of LFMS.