This multicenter, randomized, controlled study evaluated the efficacy and safety of interferon alfacon-1 (r-IFN-alphacon1) compared with lymphoblastoid interferon-alpha (IFN-alphan1) in patients with high-titer chronic hepatitis C virus (HCV) infection. Two hundred and seven patients were randomized to receive either 18 MIU (&mgr;g) r-IFN-alphacon1 or 9 MIU IFN-alphan1 daily for 2 weeks, followed by the administration of the study drugs three times weekly for 22 weeks. The primary endpoint was sustained virological response defined as the inability to detect serum HCV RNA at the end of the 24 week post-treatment observation period. In the intention-to-treat analysis, r-IFN-alphacon1 produced a slightly but not significantly higher proportion of sustained virological response than IFN-alphan1 (26.3 vs. 20.7% P=0.392). In patients with high baseline titer and genotype 1b, the proportion of sustained virological response was significantly higher in the r-IFN-alphacon1 cohort, than the IFN-alphan1 cohort (16.7 vs. 3.3%, P=0.017). The adverse events commonly reported were flu-like symptoms, anorexia, insomnia, and alopecia. Types and frequencies of the adverse events were similar in the two cohorts. The results of this study show that r-IFN-alphacon1 is an effective and tolerable therapy in patients with chronic HCV with high viral titer. The results also indicate that 18 MIU r-IFN-alphacon1 is superior in efficacy without additional toxicity to 9 MIU IFN-alphan1 in high-titer chronic HCV patients, particularly with genotype 1b.