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Deep brain stimulation (DBS) has been applied in treatment-resistant depression (TRD) as a putative intervention targeting different brain regions. However, the antidepressant effects of DBS for TRD in recent clinical trials remain controversial.We searched Scopus, EMBASE, the Cochrane Library, PubMed, and PsycINFO for all published studies investigating the efficacy of DBS in TRD up to Feb 2017. Hamilton depression rating scale (HDRS) scores and Montgomery–Asberg depression rating scale (MARDS) scores were compared between baseline levels and those after DBS using the standardized mean difference (SMD) with 95% confidence intervals (CIs). The pooled response and remission rates were described using Risk Difference with 95% CIs.We identified 14 studies of DBS in TRD targeting the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS), medial forebrain bundle (MFB), and nucleus accumbens (NAcc). The overall effect sizes showed a significant reduction in HDRS after DBS stimulation in these four regions, with a standardized mean difference of − 3.02 (95% CI = − 4.28 to − 1.77, p < 0.00001) for SCG, − 1.64 (95% CI = − 2.80 to − 0.49, p = 0.005) for VC/VS, − 2.43 (95% CI = − 3.66 to − 1.19, p = 0.0001) for MFB, and − 1.30 (95% CI = − 2.16 to − 0.44, p = 0.003) for NAcc. DBS was effective, with high response rates at 1, 3, 6, and 12 months. Some adverse events (AEs), especially some specific AEs related to targeting regions, occurred during the DBS treatment.DBS significantly alleviates depressive symptoms in TRD patients by targeting the SCG, VC/VS, MFB, and NAcc. Several adverse events might occur during DBS therapy, although it is uncertain whether some AEs can be linked to DBS treatment. Further confirmatory trials are required involving larger sample sizes.This is a systematic meta-analysis of DBS targeting all four reported brain regions including SCG, VC/VS, MFB, and NAcc in TRD.DBS significantly alleviates depressive symptoms in TRD patients.Adverse effects of DBS during TRD therapy were statistically analyzed and reported in this work.