To increase the sustained response (SR) rate in chronic hepatitis C (CHC), we tried a combination therapy with interferon (IFN) alpha and beta. Fifty patients were grouped into 4 groups: group 1H (n=9), HCV serotype 1 and high HCV-RNA titer (over 6 log copies/ml); group 1L (n=11), HCV serotype 1 and low HCV-RNA titer (less than 6 log copies/ml); group 2H (n=23), HCV serotype 2 and high HCV-RNA titer; group 2L (n=7), HCV serotype 2 and low HCV-RNA titer. They were given a total dose of 768 MIU which included natural IFN beta (6 MIU) once daily for 28 consecutive days and then natural IFNalpha (10 MIU) three times a week for 20 weeks. Forty-nine patients with CHC receiving IFN alpha at total dose of 480 MIU served as single therapy group. In combination group, SR rate was achieved in 62%, 44% in 1H, 45% in 1L, 70% in 2H, and 86% in 2L, respectively. In single group, SR rate was achieved in 45, 14, 58, 60, and 82%, respectively. There was no significant difference for SR rate between combination group and single group. However, in patients with HCV-RNA titer between 6-7 log copies/ml of 1H group, SR rate in combination group (67%, 4/6) was significantly higher than that of single group (18%, 3/17) (p<0.05). These data suggest the usefulness of combination therapy with IFN alpha and beta in CHC with serotype 1 having moderately high HCV-RNA titer.