Objective To investigate the clinical therapeutic effects and the influence on the neural activity of esophageal cancer patients with depression after repetitive transcranial magnetic stimulation (rTMS). Methods Twentytwo identified esophageal cancer patients with depression were recruited in this study and divided into single rTMS (s-rTMS) group (12 patients), and multiple rTMS (m-rTMS) group (10 patients). Patients in the s-rTMS group received one session of highfrequency rTMS (10.0 Hz, 110 % of resting motor threshold) treatment over the left dorsolateral prefrontal cortex. The m-rTMS group received rTMS in five consecutive days, with the same parameters. Comparisons of the HAMD, SDS and amplitude of low frequency fluctuation (ALFF) were carried out before and after the treatment in each group as well as between s-rTMS and m-rTMS groups after the treatment. Furthermore, correlation between the change of behavioral scores (HAMD and SDS) and the change of ALFF were also calculated. Results HAMD and SDS scores were significantly increased both in s-rTMS and m-rTMS groups after treatment (P＜ 0.05) and the mrTMS group improved more than s-rTMS group. Comparison of the ALFF between baseline and after treatment, ALFF was significantly increased in the bilateral prefrontal cortices (PFC), bilateral anterior cingulate cortex (ACC), right thalamus (THA), and the right hippocampus (HIP) in srTMS group. The ALFF was significantly increased in the bilateral PFC, bilateral ACC, right pallidum, and the right HIP in m-rTMS group after the rTMS treatment. The mrTMS group also achieved more significant improved ALFF in the bilateral PFC, bilateral ACC, and the head of the right caudate nucleus compared to the s-rTMS group (P＜0.05). The significantly negative correlation between the ALFF changes in the ACC and the HAMD score changes were observed in both groups. In addition, the significant negative correlation was found between the ALFF changes in the right HIP and the HAMD score changes in m-rTMS group (P＜ 0.05).Conclusion High frequency rTMS which is a safe method might have a positive antidepressant effect on esophageal cancer patients with depression, and the treatment using mrTMS is more effective than s-rTMS. This may be associated with the regulation of rTMS on neural physiological activities in the related brain areas, especially on the ACC and the right HIP.