OBJECTIVES: The global prevalence of hepatitis C virus (HCV) infection is estimated at over 300 million persons.  Despite stable prevalence, the economic burden in the United States (US) is projected to double over the next decade. Less is known, however, for the rest of the Americas.  These epidemiologic and economic data are critical for decision-makers to project the impacts of HCV treatments. The objective of this study was to synthesize literature-based estimates of the prevalence and economic burden of HCV from Canada, Mexico, Brazil, Argentina, Peru, Colombia, and Venezuela. METHODS: A systematic review was conducted in September 2010 to determine the a) prevalence, and b) resultant economic burden, of HCV.  Two independent reviewers extracted data from articles meeting the inclusion criteria: from EMBASE, Medline, or the Cochrane databases; focusing on general population estimates from the target countries; and published since the year 2000. RESULTS: The search strategy identified 280 abstracts; eight provided general population prevalence estimates.  In Brazil, the prevalence was estimated at 1.4% in Sao Paulo, and 3.6% in the state of Para. Canadian national surveillance programs estimated HCV prevalence at 0.8%; with provincial estimates from 1.3% to 2.0%. Mexican estimates ranged from 0.7% to 2.0%; the national health survey reported a prevalence of 1.4%. No prevalence estimates were identified for the remaining countries. Only one study (from Canada) assessed the overall economic burden. Despite a predicted 14% decrease in prevalence, HCV-related costs were projected to increase by over 50%, to 158 million dollars annually by 2040. CONCLUSIONS: HCV prevalence estimates varied from 0.8% to 3.6%, from general population based studies from Canada, Mexico, and Brazil.  Canadian data suggest the economic burden of HCV is large, and increasing. While these data are useful for decision-makers, the paucity of data for South America highlights a substantial knowledge gap.