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The increasing prevalence of intravenous drug users (IVDU) has resulted in higher incidence of right-sided infective endocarditis (RSIE). However, treatment guidelines for RSIE in IVDU are not well defined. The aim is to evaluate efficacy of different treatment strategies in reducing mortality and to describe treatment outcomes.We systematically reviewed the literature using PubMed, Cochrane, CENTRAL, OvidEMBASE, Web of Science, and Medline databases to include prospective studies that compare mortality rates among IVDU with RSIE receiving isolated medical treatment versus those receiving medical-surgical treatment. In conjunction, analysis of 27 RSIE patients (including IVDU) treated at authors' institution was done to supplement the findings. Kaplan-Meier survival rates following hospital admission and cumulative incidence estimates for hospital re-admission were obtained.A total of nine studies (all with low or marginal risk of bias) met inclusion criteria. The prevalence of RSIE among IVDU with infective endocarditis varied from 34% to 100%. Seven studies compared medical versus medical-surgical therapy with less than 30% needing surgery. Mortality was higher in patients receiving surgical therapy. There were 27 RSIE (16 non-IVDU and 11 IVDU) analyzed at the authors' institution. Survival at 30 days, 1 year, and 3 years were 89%, 82%, and 78%, respectively, and repeat hospitalization for recurrent endocarditis were 8%, 17%, and 23%, respectively.There is paucity around optimal RSIE management strategy for IVDU that can decrease mortality. Surgical management of RSIE may be associated with increased mortality over medical management mainly due to advanced surgical indications.