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Background: Tungiasis is a neglected disease caused by Tunga penetrans that can be complicated by secondary infections and local tissue destruction. Adequate treatment is important, especially in vulnerable populations; potential treatment options proposed range from surgical extraction to the use of oral and topical medications. We aimed to perform a systematic review to assess the efficacy of topical, oral and surgical interventions for the treatment of tungiasis. Methodology/Principal findings: The present review is registered in PROSPERO (CRD42021234741). On September 1, 2020, we searched PubMed, EMBASE, Scopus, Web of Science, Science Direct, Scielo and LILACS BVS. We included clinical trials and longitudinal observational studies that evaluated any topical, systemic or mechanical treatment for tungiasis. We used the Revised Cochrane Risk of Bias (RoB) Tool for Randomized Trials for clinical trial analysis. Qualitative and quantitative descriptive syntheses were performed. Our search strategy resulted in 3376 references. Subsequently, 2568 titles/abstracts and 114 full texts were screened. We finally included 19 articles; 9 were classified as clinical trials. Two and 3 articles presented low and some RoB, respectively, according to the tool. Only two articles tested the efficacy of oral medications (niridazole, ivermectin), with discouraging results. Six clinical trials evaluated topical products for the treatment of tungiasis; 2 evaluated dimeticone-based compounds and reported positive results in lesion reduction and cure. None reported significant adverse reactions. Surgical extraction was evaluated only in observational studies. Conclusions/Significance: We conclude that, although surgical extraction is the most commonly used treatment, there is sufficient evidence supporting the use of occlusive agents, especially manufactured dimeticone-based products. Author summary: Tungiasis is a disease caused by Tunga penetrans that affects regions with low socioeconomic status and a lack of proper sanitation. The disease usually has a self-limiting course or can be cured by simple extraction, but complications are not uncommon. In vulnerable populations, such as indigenous communities, children and people with disseminated tungiasis, the development of new treatment strategies is essential for the prevention of undesirable secondary outcomes. We performed a comprehensive systematic review of the literature by searching the most important scientific databases: PubMed, EMBASE, Scopus, Web of Science, Science Direct, Scielo and LILACS BVS. We aimed to assess the efficacy of topical, oral and surgical interventions for the treatment of tungiasis. We included 19 articles, 9 of which were classified as clinical trials. Six clinical trials evaluated topical products for the treatment of tungiasis; 2 evaluated dimeticone-based compounds and reported positive results in lesion reduction and cure. None reported significant adverse reactions. We concluded that, although mechanical extraction is the most commonly used treatment, there is sufficient evidence supporting the use of occlusive agents, especially manufactured dimeticone-based products. [ABSTRACT FROM AUTHOR]