OBJECTIVES To compare productivity, absence days, and absence costs for treated (HCV-Tx) and untreated (HCV-NoTx) US employees with hepatitis C virus (HCV) infection. STUDY DESIGN Retrospective database study. METHODS Employee records from multiple large employers in the United States with data about demographics, jobs, and healthcare use in the Human Capital Management Services database were assessed. HCV subjects were identified by International Classification of Diseases, 9th Revision codes. To test differences between cohorts, t tests and χ2 tests were used. Regression modeling was used to compare absence days, costs,and objectively measured productivity, while controlling for confounding factors. For HCV-Tx employees, the index date was the date of the first treatment with interferon, peginterferon, and/or ribavirin. For HCV-NoTx employees, the index date was the average date by company among HCV-Tx employees. Absence and productivity were measured from each employee's index date to the last date the employee was enrolled in health benefits coverage. RESULTS A total of 441 HCV-Tx and 1223 HCV-NoTx employees were evaluated. HCV-Tx workers had 0.52 more total monthly absence days and $31.31 in additional monthly absence payments per employee than untreated employees. Treated employees' productivity was lower, with treated subjects processing 11.7% fewer units per hour and 17.4% fewer units per month than untreated employees. CONCLUSIONS This study quantified the substantial indirect burden of illness associated with use of current HCV treatments. New treatments are needed with improved adverse effect profiles that result in reduced absence from work and improved productivity among HCV-infected persons.