Less than 10% of patients with chronic hepatitis C infected with genotype 1 achieve a sustained response with 12 months of interferon therapy. Viral kinetics studies have shown that HCV may replicate in less than 24 hr, generating over 10(12) copies per day and suggesting the need for more aggressive therapy. The aim of the study was to determine the effect of a higher and daily dosage of IFN-alpha2b plus ribavirin on the viral load and on the response rate in patients infected by genotype 1 and previous nonresponders to interferon. Ten patients with chronic hepatitis C infected with genotype 1 were allocated to receive IFN-alpha2b, 5 MU daily or three times a week for four weeks followed by 5 MU three times a week until week 24 plus ribavirin for the entire period. At week 4 of therapy, a 2 log reduction in HCV RNA levels was achieved in three (60%) patients in the daily group and in one (20%) patient in the three times a week group. At week 24, HCV RNA was negative in four of the five patients in the three times a week group, and three of the four patients in the daily group had a virological response. However, in follow-up, none of these patients experienced a sustained response. The safety of and ability to tolerate the combination therapy was good, anemia being the most common adverse effect. In conclusion, patients previously not responding to interferon achieved a greater virological reduction early in combination therapy compared to a three times a week interferon schedule. However, the virological response at the end of therapy was similar between the two regimens, and no sustained response was observed in any of the treatment groups.