A substantial proportion of patients with chronic hepatitis C virus (HCV) infection (HCV RNA positive) have persistently normal serum alanine aminotransferases (ALT). These patients currently pose a therapeutic dilemma, as it is not clear how best to deal with them. Response rates to interferon are low, and in some cases interferon therapy has been associated with an increase in serum aminotransferases. Therefore, the NIH Consensus Conference recommended against treating them with interferon. Although most patients with persistently normal serum ALT levels have mild disease on liver biopsy, the consensus panel did think it appropriate to do liver biopsies in these subjects. Few data are available on therapy with the combination of interferon and ribavirin for such patients. At Saint Louis University, 24 patients with normal ALT were treated with interferon/ribavirin. Preliminary analysis of the results shows that 33% of the patients had a sustained response 24 weeks after therapy. Thus, uncertainties remain about patients with chronic HCV infection and persistently normal serum ALT with the currently available therapies. However, if a more effective and better tolerated therapy were to become available, such patients might best be treated to eliminate the chronic viral infection.