Patients with chronic hepatitis C who do not respond to interferon can be treated with glycyrrhizin to reduce disease activity. The objective of this study was to evaluate the effect of glycyrrhizin on the incidence of hepatocellular carcinoma (HCC) during long-term follow-up after non-response to interferon. We analyzed individual patient data of all consecutive patients treated with interferon in 12 major Japanese hospitals between 1990 and 1995 who showed no sustained response. The study comprised 1093 patients. During a mean follow-up of 6.1±1.8 years, 107 patients developed HCC. The Cox regression analysis with time-dependent variables showed that older age, male gender, higher alanine aminotransferase (ALAT) and higher fibrosis stage were significantly associated with a higher risk of developing HCC. Response to glycyrrhizin, defined as ALAT < 1.5×upper limit of normal, was significantly associated with a decreased incidence of HCC: hazard ratio 0.39 (95% CI 0.21–0.72; p<0.01). G-estimation, used to correct for ALAT as the confounder, showed no significant benefit of glycyrrhizin in the overall study population. This study provides some evidence to show that interferon non-responder patients with chronic hepatitis C and fibrosis stage 3 or 4 may have a reduced incidence of HCC if glycyrrhizin therapy leads to normalization of ALAT levels.