The aim of this study is to determine whether early viral dynamics and evolution predict outcome of primary acute hepatitis C virus (HCV) infection. HCV‐ and human immunodeficiency virus–negative injection drug users were enrolled prospectively and followed monthly to identify acute HCV infection using RNA detection. Subjects with more than 1 month between HCV‐RNA‐negative and ‐positive visits were excluded to ensure stringent acute infection. Differences in medians of log‐transformed viral RNA levels and evolutionary rates in each gene of a 5′‐hemigenomic amplicon were assessed using Mann‐Whitney's rank‐sum test. Correlation coefficient was calculated using Spearman's rank order. Initial viremia level was 50‐fold higher in subjects with spontaneous clearance (compared with persistence) of primary acute HCV infection (median, 7.1 versus 5.4 log₁₀ IU/mL; P = 0.002). Initial viremia level in subjects with interleukin (IL)28B‐C allele at rs12979860 and clearance was higher than that in subjects with IL28B‐T allele and persistence (P = 0.001). Evolutionary rates in the hypervariable region 1 (HVR1) region of the E2 gene were significantly higher in self‐resolvers than those in persistence subjects during early infection, whereas other genes or regions had comparable rates. All major substitutions in HVR1 in persistence subjects were convergent changes, whereas over the same time interval clearance subjects displayed divergent evolution, indicating different immune responses between the two groups. Conclusion: Spontaneous clearance of acute HCV infection is predicted by high initial viremia as well as favorable IL28B genotype and is associated with rapid envelope‐sequence evolution. This linkage of host genetics, viral dynamics, and evolution provides new directions for mechanistic studies. (HEPATOLOGY 2012;55:1684–1691)