The objective of this study is to determine the efficacy and safety of peginterferon alfa-2a (40KD)/ribavirin in patients with advanced fibrosis. Data from 341 genotype 1/4 patients (99 with bridging fibrosis/cirrhosis) treated for 48 weeks and 1547 genotype 2/3 patients (380 with bridging fibrosis/cirrhosis) treated for 16 or 24 weeks enrolled in three randomized international studies were analyzed. Sustained virological response (SVR) rates decreased progressively from 60% in genotype 1/4 patients without advanced fibrosis to 51% in those with bridging fibrosis and 33% in those with cirrhosis (trend test P = 0.0028); and from 76% to 61% and 57%, respectively, in genotype 2/3 patients treated for 24 weeks (trend test P < 0.0001). Irrespective of genotype, patients without advanced fibrosis were more likely to have an earlier response to treatment that was associated with higher SVR rates and lower relapse rates during untreated follow-up. Among patients with or without a diagnosis of advanced fibrosis, rates of SVR and relapse were similar for patients with similar responses in the first 12 weeks. Conclusion: Compared with patients with less severe disease, SVR rates are significantly lower in patients with advanced fibrosis. However, irrespective of genotype and degree of fibrosis, the time to become hepatitis C virus (HCV) RNA undetectable was the strongest predictor of SVR. (HEPATOLOGY 2010.)