Abstract The purpose of the first study was to compare the efficacy and safety of peginterferon alfa-2a (PEG IFN) administered once per wk for 48 wk s.c., with IFN alfa-2a administered three times/wk. The primary efficacy endpoints were a sustained virologic response (indicated by 3 (ALT quotient being the average of the serum ALT values before treatment divided by the upper limit of normal), and HCV genotype other than 1. The frequency and severity of adverse effects were similar in the two groups. Psychiatric disorders were the most frequent serious adverse events, and significant anemia or thrombocytopenia was rare in both treatment groups. In the second study the efficacy and safety of PEG IFN alfa-2a in patients with HCV-related cirrhosis (76–79%) or bridging fibrosis (20–24%) were studied. In this multicenter, open label, randomized, parallel dose study, 271 patients with cirrhosis or bridging fibrosis were randomly assigned to receive treatment with 3 million U of IFN alfa-2a three times weekly (n = 88 patients), 90 μg of PEG IFN alfa-2a once weekly (n = 96), or 180 μg of PEG IFN alfa-2a once weekly (n = 87). Treatment was given for 48 wk and patients were observed thereafter for 24 more wk. Patients with decompensated cirrhosis, HIV infection, cancer, neutrophil count of 100 ng/ml were excluded from the study. The primary endpoints and their definitions were similar to those in the study by Zeuzem et al. The secondary endpoints included virological and biochemical responses at the end of the 48-wk treatment period. Histological changes were also accessed on a 22-point Histological Activity Index (inflammation graded from 0 to 18 and fibrosis graded from 0 to 4) and defined as a positive response based on a ≥2 point decrease in the total score. Treatment was completed by 64, 78, and 67 patients, respectively, in the three groups, and follow-up was completed by 68, 79, and 74 patients, respectively, in the three groups. The rates of sustained virological response were 8%, 15%, and 30% in patients assigned to unmodified IFN alfa-2a, 90 μg of PEG IFN alfa-2a, and 180 μg of PEG IFN alfa-2a, respectively (p = 0.001 for comparison between the first and third groups). However, among patients infected with genotype 1, the response rates were 2%, 5%, and 13% in the three groups (genotype 1b had a 2-fold better response rate than 1a). It is also of note that a response at wk 12 predicted a sustained response. The rates of sustained biochemical response were 15%, 20%, and 34% in the three groups (p = 0.004 for comparison between the first and third groups). Among the patients who had paired liver biopsies, the histological responses were 31%, 44%, and 54% in patients assigned to unmodified interferon alfa-2a, 90 μg of PEG IFN alfa-2a, and 180 μg of PEG IFN alfa-2a, respectively (p = 0.02 for comparison between the first and third groups). A histological response correlated with a sustained virologic response (80–100%). The virological response was similar among patients with either bridging fibrosis or cirrhosis. Of interest, a histological response was also seen in about 26–35% of patients who did not have a sustained virological response. Even in the cohort of patients with a combination or poor prognostic factors (genotype 1, high baseline viral load of >2.0 million copies/ml), 10% of patients assigned to 180 μg of PEG IFN alfa-2a had a sustained virologic response. Safety parameters were carefully evaluated, and the proportion of patients with a neutrophil count of