Protease inhibitor with pegylated interferon and ribavirin therapy (PI-PR) increases hepatitis C virus treatment efficacy versus standard of care pegylated interferon and ribavarin therapy [PR]. The adverse event (AE) impact of PI-PR remains under-reported. The authors estimated the AE impact on costs, treatment discontinuation and health-related quality of life (HRQoL) in PI-PR- and PR-treated patients through literature review and cost analysis. HRQoL and safety data were synthesized by instrument, AE and discontinuation rate. AE-related treatment costs were estimated with trial-based AE rates and literature-based protocols, resource utilization and standard costs. No PI-PR study reported HRQoL outcomes. Five PR studies reported that anemia, depression, fatigue and/or influenza-like symptoms negatively affected HRQoL. Decreased HRQoL predicted treatment discontinuation in two PR studies. PI-PR and PR had comparable AE-related treatment discontinuation rates (~12%). Weighted AE-related treatment costs were US$2042, $1835 and $1076 in boceprevir-based PI-PR, PR and telaprevir-based PI-PR, respectively. AE-related burden may increase with PI-PR. Future studies should incorporate AE-related economic and HRQoL outcomes to comprehensively assess costs/benefits.