Hepatitis C virus (HCV) infection in prisoners represents an important public health problem. However, there is very little information about HCV-related health-related quality of life (HRQOL). We examined the effect of HCV antibody positivity, HCV viremia, and being a prisoner on prisoners'' HRQOL. Population-based health surveys incorporating HCV screening were conducted among prisoners at New South Wales (NSW), Australia, correctional centers in 1996 and 2001. HCV antibody and HCV RNA status were determined from venous blood sampling. HRQOL and mood status were assessed using the Short Form-36 (SF-36) Health Survey and Beck Depression Inventory (BDI). Comparison of HRQOL scores between HCV antibody negative, HCV antibody positive/non-viremic, and HCV antibody positive/viremic and assessment of temporal change in HRQOL between 1996 and 2001 within groups were made using ANCOVA adjusting for confounders. Factors associated with HRQOL were determined in linear regression models. Analyses between HCV antibody negative (n = 423), HCV positive/non-viremic (n = 89), and HCV positive/viremic (n = 178) prisoners found no measurable effect of HCV on HRQOL, including that attributable to HCV viremia. Compared to uninfected Australian population norms, prisoners had lower HRQOL irrespective of HCV status. The prevalence of ‘moderate’ to ‘severe’ depressive symptoms was greater in the HCV antibody positive/viremic group than the HCV antibody positive/non-viremic group or the HCV antibody negative group. Selected demographic factors (age), co-morbidity, severity of depressive symptoms and medical care utilization influenced HRQOL. There was evidence to support the effect of knowledge of HCV status on HRQOL. In conclusion, our findings contrast with previous studies in non-prisoner groups in which HCV infection appears to decrease overall HRQOL. Non-HCV factors may override HCV-specific HRQOL impairment in this population. Targeted management strategies are required to improve HRQOL of prisoners.