OBJECTIVES: To indirectly estimate the relative treatment effect of 12 weeks of treatment with SMV versus TPV in combination with response-guided background therapy of 24/48 weeks of Peginterferon/ribavirine (PR) in previously untreated patients with genotype 1 chronic hepatitis C virus infection, using patient-level data from the pivotal phase III-trials. METHODS: Patient-level data from three phase 3 trials in treatment-naive patients were pooled: ADVANCE  (12 weeks of TPV-treatment (T12PR24/48)) and QUEST 1&2 (12 weeks of SMV-treatment (SMV12PR24/48) (with PR24/48 meaning response-guided duration of PR of 24 or 48 weeks). To adjust for potential differences in patient characteristics across both trials, an adjusted odds ratio (OR) for reaching sustained viral response at week 24 (SVR24) was estimated for a multivariate logistic regression model,  including genotype (G1a vs G1b), liver status (F0-2 vs F3-4),  race (white, black, other), viral load (<273K/273-<800K/800-<1200K/≥1200K IU/ml), age (≤45/45<-≤65/>65), gender and BMI (<25/25-<30/30+) as baseline covariates. As a sensitivity analysis, a similar analysis was generated excluding SMV-G1a patients with Q80K-polymorphism. RESULTS: Patient numbers for T12PR24/48 and SMV12PR24/48 were 363 and 521 respectively. 16.3% (n=85) of SMV-patients were G1a with Q80K-polymorphism. Overall, G1a (OR vs 1b =0.75, p=0.01), peg-interferon alpha-2b (OR vs peg-interferon alpha-2a =0.60, p=0.03), F3-4 liver status (OR vs F0-F2=0.48, p<0.0001), black race (OR vs white race =0.56, p<0.001) and viral load  ≥1200K (OR vs <273K =0.28, p<0.0001) were significantly associated with lower SVR24-rates. The observed SVR24-rates were 75% (TVR) versus 80% (SMV) (unadjusted OR=0.75). The adjusted OR for T12PR24/48 to reach SVR24 compared to SMV12PR24/48 was 0.64 [95% CI: 0.46;0.91]  (p=0.0113). When excluding Q80K-positive patients, the adjusted OR was 0.45 [0.31;0.67] (p<0.0001). CONCLUSIONS: In absence of H2H-comparison of telaprevir versus simeprevir in treatment-naive patients, an adjusted indirect comparison using patient-level data suggests significantly higher SVR24 response rates for patients treated with simeprevir compared to telaprevir.