Serum gammaGT levels and hepatic expression of tumor necrosis factor-alpha (TNF-alpha) are host factors that can independently predict the outcome of interferon (IFN) treatment in patients with chronic hepatitis C virus (HCV) infection. To explore whether a correlation exists between these two factors, we measured pretreatment gammaGT levels in serum and TNF-alpha mRNA levels in liver biopsies of chronic HCV patients. Seventy-two HCV patients treated with 3-to-5 million units of IFN-alpha three times a week were enrolled in the study. Treatment lasted 24 weeks and was followed by a 48-week follow-up period. Efficacy was assessed by measuring HCV RNA and alanine aminotransferase by the end of follow-up. Twelve patients (16.6%) showed a sustained biochemical and virological response. Normal pretreatment gammaGT levels, low HCV RNA titer, and infection with genotype other than HCV-1 were shown to be independent predictors of sustained response. Hepatic levels of TNF-alpha mRNA, quantified by polymerase chain reaction, were significantly higher in nonresponders (3.44 arbitrary units) compared to sustained responders (1.84 arbitrary units; P = 0.009). Values </=3.12 arbitrary units independently predicted a sustained response to IFN (P = 0.014). Finally, TNF-alpha mRNA levels were significantly correlated with serum gammaGT levels (r = 0.79, P < 0.0001). These findings suggest that serum gammaGT levels may represent a surrogate marker of hepatic TNF-alpha expression, thus explaining the importance of serum gammaGT levels in predicting treatment outcome.