<b><i>Background:</i></b> Obesity has become a major public health concern worldwide, with current behavioral, pharmacological, and surgical treatments offering varying rates of success and adverse effects. Neurosurgical approaches to treatment of refractory obesity include deep brain stimulation (DBS) on either specific hypothalamic or reward circuitry nuclei, which might contribute to weight reduction through different mechanisms. We aimed to determine the safety and clinical effect of DBS in medical refractory obesity. <b><i>Summary:</i></b> Adhering to PRISMA guidelines, we performed a systematic review to identify all original studies – observational and experimental – in which DBS was performed to treat refractory obesity. From database inception to April 2021, we conducted our search in PubMed, Scopus, and LILACS databases using the following MeSH terms: “Obesity” OR “Prader-Willi Syndrome” AND “Deep Brain Stimulation.” The main outcomes were safety and weight loss measured with the body mass index (BMI). The Grading of Recommendations Assessment, Development, and Evaluation methods were applied to evaluate the quality of evidence. This study protocol was registered with PROSPERO ID: CRD42019132929. Seven studies involving 12 patients met the inclusion criteria; the DBS target was the nucleus accumbens in four (57.1%), the lateral hypothalamic area in two (29.6%), and the ventral hypothalamus in one (14.3%). Further, 33% of participants had obesity secondary to Prader-Willi syndrome (PWS) and 66.6% had primary obesity. The global BMI average at baseline was 46.7 (SD: 9.6, range: 32.2–59.1), and after DBS, 42.8 (SD: 8.8, range: 25–53.9), with a mean difference of 3.9; however, the delta in PWS patients was −2.3 and 10 in those with primary obesity. The incidence of moderate side effects was 33% and included manic symptoms (<i>N</i> = 2), electrode fracture (<i>N</i> = 1), and seizure (<i>N</i> = 1); mild complications (41.6%) included skin infection (<i>N</i> = 2), difficulties falling asleep (<i>N</i> = 1), nausea (<i>N</i> = 1), and anxiety (<i>N</i> = 1). <b><i>Key Messages:</i></b> Despite available small case series and case reports reporting a benefit in the treatment of refractory obesity with DBS, this study emphasizes the need for prospective studies with longer follow-ups in order to further address the efficacy and indications.
