OBJECTIVES: To compare indirect and MTC meta-analysis techniques used in the evaluation of the protease inhibitors, boceprevir and telaprevir, in combination with peginterferon alfa and ribavirin for the treatment of patients with genotype 1 chronic Hepatitis C. METHODS: A systematic search of the literature was conducted in EMBASE and MEDLINE (January 2008 to May 2012) to identify studies that utilised either indirect or MTC meta-analysis techniques to derive the relative treatment effect between boceprevir and telaprevir. A qualitative comparison was made between the methodologies and results of the identified studies. RESULTS: Two publications were identified: a conference poster (Diels et al.) and a full publication (Cooper et al.). The main difference between the methodologies is that Cooper et al. used an adjusted indirect comparison and a random-effects MTC model whereas Diels et al. used a fixed-effects MTC model. Diels et al. included three further studies that compare peginterferon alfa-2a and alfa-2b without active therapies. Cooper et al. conducted a random-effects adjusted indirect comparison that included two additional telaprevir trials that were excluded from Diels et al. The primary outcome in both studies was the proportion of patients achieving sustained virologic response. Diels et al. reported no significant difference in treatment naive patients and a significant effect in favour of telaprevir for treatment experienced patients. When Diels et al. applied a random-effects model the effect of telaprevir being superior in treatment experienced patients was non-significant. The results reported by Cooper et al. showed no significant difference between boceprevir and telaprevir, and did not vary in sensitivity analyses. CONCLUSIONS: Comparison of these two studies highlights considerable methodological differences between the two approaches, which result in differing conclusions. While MTC methods are growing in popularity and importance, certain nuances of approaches can result in important differences in interpretation.