This study presents a comprehensive epidemiologic model of hepatitis C in the United States. Through empirical calibration of model parameter values, the objectives were to gain insights into uncertain aspects of the natural history of hepatitis C and to improve the basis for projecting the future course of the epidemic. A systematic review of the published literature was conducted to define plausible ranges around model parameters, and multiple simulations of the model were undertaken using sampled values from these ranges. Model predictions produced by each set of sampled values were compared with available epidemiologic data on infection prevalence and mortality from liver cancer, and various goodness-of-fit criteria were used to identify the range of parameter values that were consistent with these data. The results of the study indicate that rates of progression to advanced liver disease may be lower than previously assumed. The authors also found that a wide range of plausible assumptions about heterogeneity in these rates, beyond that explained by age and sex, is consistent with observed epidemiologic trends. These findings have important implications both for individual clinical decisions and for broader public health policy.