BACKGROUND: Hepatitis C virus (HCV) infection causes significant morbidity and mortality among people who inject drugs (PWID) and HIV+ men who have sex with men (MSM). Characterizing spontaneous viral clearance of HCV infection among PWID and HIV+ MSM is important for assessing the burden of disease and treatment strategies in these populations. METHODS: Electronic and other searches of medical literature were conducted. Reports were eligible if they presented original data from upper-middle- and high-income countries on laboratory-confirmed HCV infection and spontaneous viral clearance among PWID or HIV+ MSM. Pooled estimates of spontaneous viral clearance were generated using fixed-effect and random-effects models. Meta-regression examined potential predictors related to individual characteristics and research methodology. RESULTS: The meta-analysis estimated that spontaneous viral clearance occurs in 24.4 % of PWID and 15.4 % of HIV+ MSM. In univariate meta-regression among PWID, male sex and age were significantly associated with spontaneous viral clearance, and in multivariate analysis, male sex and HIV positivity were predictors of spontaneous viral clearance; among HIV+ MSM no variables were found to affect spontaneous viral clearance. CONCLUSION: The variability in estimates of spontaneous viral clearance between HIV+ MSM and PWID suggests the impact of HIV co-infection and HCV re-infection. Due to limited data on additional factors that may affect the natural history of HCV, more research is needed to further understand spontaneous viral clearance in these risk groups. PROTOCOL REGISTRATION: The protocols for the PWID and HIV+ MSM research were registered with PROSPERO (CRD42014008805; CRD42013006462).