The aim of this work was to estimate the future disease burden of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections in the United States until the year 2030. Two back-calculation models of the HIV and the HCV epidemic were developed. They were based on US epidemiological data regarding prevalence, age and gender of incident cases, AIDS, hepatocellular carcinoma (HCC) mortality and general population mortality from the Centers for Disease Control and WHO. Based on the HCV back-calculation model, HCV incidence peaked in 1984 at 350,000 new infections and then fell to about 77,000 in 1998. Based on the HIV back-calculation model, HIV incidence reached its maximum in 1989 at 142,000 new infections and then declined to 79,000 in 1998. Mortality related to HCV (death from liver failure or HCC) rose from about 3,700 in 1998 and is expected to peak at about 13,000 in 2030. Predicted HCV mortality would fall only if increased access to or more effective antiviral therapy occurs. For comparison, observed HIV-related mortality was 14,400 in 1998 and projected to be 4,200 for 2030. With the availability of effective highly active antiretroviral therapy for HIV infection, mortality from HIV appears to have declined substantially, whereas HCV-related deaths as a result of pre-1999 infections will likely continue to increase over the next 25 years.