Treatment response remains suboptimal for many patients with chronic hepatitis C, particularly those with genotype 1 and high levels of viremia. The efficacy of high-dose regimens of peginterferon alfa-2a and ribavirin was compared with conventional dose regimens in patients with features predicting poor treatment responses. Eligible treatment-naı ¨ve adults with genotype 1 infection, hepatitis C virus (HCV) RNA >800,000 IU/mL and body weight >85 kg were randomized to double-blind treatment with peginterferon alfa-2a at 180 or 270 g/week plus ribavirin at 1200 or 1600 mg/day for 48 weeks (four regimens were evaluated). The primary endpoint was viral kinetics during the first 24 weeks of therapy. Among patients receiving peginterferon alfa-2a (270 g/week) the magnitude of HCV RNA reduction was significantly greater than for patients randomized to the conventional dose of peginterferon alfa-2a (180 g/week) for the pairwise comparison for ribavirin at 1600 mg/day (P ؍ 0.036) and numerically greater for the pairwise comparison for ribavirin at 1200 mg/day (P ؍ 0.060). Patients randomized to the highest doses of peginterferon alfa-2a (270 g/week) and ribavirin (1600 mg/day) experienced the numerically highest rates of sustained virologic response (HCV RNA < 50 IU/mL) and the lowest relapse rate (47% and 19%, respectively). The arm with the higher doses of both drugs was less well-tolerated than the other regimens. Conclusion: Higher fixed doses of peginterferon alfa-2a (270 g/week) and ribavirin (1600 mg/day) may increase sustained virologic response rates compared with lower doses of both drugs in patients with a cluster of difficult-to-treat characteristics. (HEPATOLOGY 2008;48:1033-1043.) T herapy of chronic hepatitis C with peginterferon and ribavirin yields an overall sustained virologic response (SVR) rate between 54%-56%. [1][2][3] Numerous virologic and host factors have been identified that have a substantial impact on the likeli-hood of achieving an SVR. Genotype 1 and baseline levels of hepatitis C virus (HCV) RNA above 800,000 IU/mL are the strongest factors associated with diminished response rates. 1-3 Among host characteristics, the presence of cirrhosis, African American race, obesity,