Immunosuppressive therapy increases levels of hepatitis C virus (HCV) RNA, and when combined with interferon, corticosteroids have been reported to variably improve or have no effect on sustained response rates. We conducted a randomized double-blind placebo-controlled trial in 39 patients with biopsy-proven chronic HCV infection and elevated alanine aminotransferase levels. Patients received either 6 weeks of a tapering dose of prednisone (60 ng, 40 mg, and 20 mg in 2-week intervals) or an identical placebo. All patients then received recombinant interferon alpha-2b, 3 million units three times a week for 24 weeks. Patients were then followed for a further 24 weeks. At the end of the study there was no significant difference in the sustained biochemical response rates between the two groups (4/20 vs. 3/19, p value was not significant). Prednisone-treated patients had a significant increase in HCV RNA from baseline during steroid treatment (400 +/- 60% increase vs. -280 +/- 140% decrease; p = 0.005). Two prednisone-treated patients were withdrawn from the study secondary to serious complications related to therapy. Prednisone priming before interferon alpha therapy in patients with chronic HCV infection does not improve the sustained response rate. This therapy was associated with an increase in viral burden and significant morbidity.