This study assessed the effect of chronic hepatitis C virus (HCV) infection on the health-related quality of life (HRQOL) of injecting drug users, comparing the HRQOL of injecting drug users with and without chronic HCV infection. The study included 199 injecting drug users of more than 18 years of age who participated in a needle exchange program. Blood samples were tested for the presence of HCV RNA in serum with a polymerase chain reaction method. HRQOL was measured using the questionnaire SF-36, measuring HRQOL over the last 4 wk. The HCV RNA test was positive in 102 (51%) and negative in 97 (49%) subjects. The HRQOL scores of actively injecting drug users were markedly reduced compared to the population norm. However, we did not find poorer HRQOL in injecting drug users with chronic HCV infection than in injecting drug users without HCV infection. HCV RNA positive injecting drug users who were aware of the infection had lower HRQOL scores than those unaware of the infection in 4 of the 8 SF-36 dimensions (general health, physical functioning, physical role, and vitality). HCV RNA negative subjects, who believed they were infected, scored worse in one dimension (general health) compared to those who did not believe they were infected. In conclusion, chronic HCV infection per se did not negatively affect the HRQOL of active injecting drug users. Those who thought they were infected had a lower HRQOL scores than those who believed they were not infected.