The disease burden and mortality from hepatitis C are predicted to increase in the United States as the number of persons with long-standing chronic infection grows. We analyzed hepatitis C mortality rates derived from US Census and multiple-cause-of-death data for 1995-2004. Deaths were considered hepatitis C-related if: (1) hepatitis C was the underlying cause of death, (2) chronic liver disease was the underlying cause and hepatitis C was a contributing cause, or (3) human immunodeficiency virus was the underlying cause and chronic liver disease and hepatitis C were contributing causes. A total of 56,409 hepatitis C-related deaths were identified. Mortality rates increased 123% during the study period (1.09 per 100,000 persons to 2.44 per 100,000), but average annual increases were smaller during 2000-2004 than 1995-1999. After peaking in 2002 (2.57 per 100,000), overall rates declined slightly, but continued to increase among persons aged 55-64 years. Overall increases were greater among males (144%) than females (81%) and among non-Hispanic blacks (170%) and Native Americans (241%) compared to non-Hispanic whites (124%) and Hispanics (84%). The 7,427 hepatitis C deaths in 2004 (mean age: 55 years), corresponded to 148,611 years of potential life lost. The highest mortality rates in 2004 were observed among males, persons aged 45-54 and 55-64 years, Hispanics, non-Hispanic blacks, and non-Hispanic Native American/Alaska Natives.Overall, hepatitis C mortality has increased substantially since 1995. Despite small declines in recent years, rates have continued to increase among persons aged 55-64 years. Hepatitis C is an important cause of premature mortality.