Rapid virologic response (RVR) and complete early virologic response (cEVR) are associated with sustained virologic response to hepatitis C virus (HCV) therapy. We retrospectively examined baseline and on-treatment factors associated with RVR (HCV RNA undetectable at week 4) and cEVR (HCV RNA undetectable at week 12, regardless of week 4 response). The analysis comprised 1550 HCV genotype-1 patients from five clinical trials, including three enriched with difficult-to-treat populations, randomized to peginterferon alfa-2a 180 microg/week plus ribavirin 1000-1200 mg/day. Overall, 15.6% achieved RVR and 54.0% achieved cEVR. Baseline factors predictive of RVR were serum HCV RNA <or= 400,000 IU/mL (OR: 7.34; P < 0.0001), alanine aminotransferase >3 x ULN (OR: 2.01; P < 0.0001), non-cirrhotic status (OR: 1.92; P = 0.0087), age <or= 40 years (OR: 1.56; P = 0.0085), white non-Latino ethnicity (OR: 1.41; P = 0.0666) and individual study (P < 0.0001). These factors plus body mass index <or= 27 kg/m(2) were predictive of cEVR. After adjusting for these factors, mean on-treatment ribavirin dose >13 mg/kg/day was predictive of RVR (OR: 1.69; P = 0.005) and cEVR (OR: 1.24; P = 0.09), whereas peginterferon alfa-2a dose reduction was not. Greater decreases in haematologic parameters were observed in patients who achieved cEVR compared with patients who did not. In conclusion, several baseline and on-treatment factors were associated with RVR and cEVR to peginterferon alfa-2a plus ribavirin in difficult-to-treat HCV genotype-1 patients, providing important prognostic information on the antiviral response in a patient cohort that is reflective of the general chronic hepatitis C population.