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Background: Most hepatitis C virus (HCV) infections in the United States occur following non-sterile injection drug use. However, the majority of people who inject drugs (PWID) with chronic HCV are not currently receiving care. Objective: This paper presents our protocol for the systematic review and meta-analysis of data on the natural history of HCV among PWID and will inform modeling of the impact and cost-effectiveness of HCV management among this population. This study is conducted as part of the HCV Synthesis Project, which is funded to develop recommendations for HCV control strategies in the United States. Methods: This protocol describes the methods used for a systematic review and meta-analysis of published and unpublished data on the natural history of HCV among PWID including viral clearance, fibrosis progression, and the incidence of compensated cirrhosis (CC), decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver-related mortality. Results: Final results are anticipated by December 2016. Conclusions: Methods used for the synthesis of data on disease progression among HCV mono-infected PWID are presented. Data from the systematic review and meta-analysis will be used to inform simulations of the natural history of HCV and to model the effects of prevention and treatment strategies to reduce disease burden and the associated costs to society and individual patients. [JMIR Res Protoc 2015;4(2):e68]