OBJECTIVES: To systematically analyze the literature to assess the economic and health-related quality of life (HRQoL) impact of adverse events (AEs) related to the addition of protease inhibitors (PI) to standard of care (SOC) for the treatment of hepatitis C (HCV). METHODS: A literature search (2000-Present) was conducted to identify and analyze clinical trials for PI triple therapy (PITT=PI+SOC) and SOC (PEGIFN/RBV for 48 weeks). HRQoL and safety data were synthesized by study design, sample characteristics, and AEs.  Economic and resource use data were synthesized in an economic analysis of AEs in PITT vs. SOC. Costs (2009) were derived from published literature. RESULTS: Twenty-three SOC and 7 PITT trials were identified. Statistically significant (p = or <0.05) changes from baseline were most often seen in trials of SOC in the following domains: vitality, depression, physical limitations, and fatigue.  The following 4 PITT-related AEs could be linked to HRQoL domains: anemia and depression were linked to fatigue and vitality, and headache and rash were linked to physical limitations. In terms of economic impacts, the costs to manage a PITT-related episode of anemia, depression, diarrhea, and rash were $4825, $2837, $566, and $633, respectively. The average AE cost in PITT ranged from $1732 to $3578. Corresponding costs in SOC ranged from $1608 to $2229. The treatment costs of PITT-related AEs were 30% (range 8-60%) higher than the cost of treating SOC-related AEs. CONCLUSIONS: The costs to manage PITT-related AEs appear higher than the costs of SOC-related AEs. Since PITT is associated with higher AE rates, it can also be expected to result in worse HRQoL.  Gaps in symptom burden assessment with existing instruments also exist. Future studies should incorporate the economic burden of AEs and the appropriate use of HCV-validated instruments to capture potential HRQoL differences among treatment strategies.