OBJECTIVES: In absence of head-to-head trials and over hundred new molecules in clinical development for hepatitis C virus (HCV) infection, mixed treatment comparisons continue to play a crucial role in guiding clinical decision making. This study was aimed to identify the practical challenges of conducting mixed treatment comparisons in chronic HCV genotype-1 patients, especially in subgroups with clinical factors that are associated with poor treatment response and/or increased risks. METHODS: A systematic review was conducted to identify randomized controlled trials of telaprevir (TVR) and boceprevir (BOC) in HCV genotype-1 patient population. Included clinical trials were assessed to check: 1) if clinical factors related to poor treatment response (race, prior viral load, grade of underlying cirrhosis/fibrosis) were reported and subgroup analyses were conducted; and 2) if important safety endpoints (rash, anemia, neutropenia) were reported with a clear definition of the gradient of severity. RESULTS: A total of eight trials were identified: five in treatment-naïve patients (4TVR, 1BOC) and three in treatment-experienced patients (2TVR, 1BOC). Among the seven trials which reported the proportion of African Americans and information on grade of fibrosis, two did not conduct subgroup analyses accordingly. Of the trials reporting prior viral load (8) and cirrhosis (5), only three and two trials presented related subgroup analyses, respectively. Severity of important safety endpoints such as rash and anemia was not defined in four of the studies (50%), mainly telaprevir trials, and neutropenia was not defined in almost two-thirds (5/8). CONCLUSIONS: From an already small pool of studies to begin with, unavailability of data and lack of safety endpoint definitions are challenges that may reduce the feasibility and increase potential biases for conducting mixed treatment comparisons. Overcoming these identified challenges will improve understanding of the comparative efficacy and safety of HCV drugs, particularly in the at-risk population.