To assess whether interferon-α might prevent non-A, non-B hepatitis from becoming chronic, 45 consecutive patients with transfusion-associated hepatitis were enrolled in a randomized clinical trial. Thirty-eight patients had hepatitis C virus infection, and 7 had non-A, non-B, non-C hepatitis. Twenty-six patients (22 with HCV) were given 3 MU of recombinant interferon-α2b three times a week for 12 wk, whereas 19 (16 with HCV) were not. Biochemical and virological parameters were monitored at regular intervals during an 18-mo follow-up. At the end of the 3-mo therapy, 16 (73) patients with hepatitis C had normal serum ALT activity, compared with 7 (44) who were not treated (NS). Fifty-three percent of the treated patients and none of the untreated patients had normal ALT levels and no HCV RNA (p = 0.0087). At the end of the 18-mo follow-up, 13 (59) treated patients had normal ALT levels, compared with 6 (37) untreated controls (NS). Thirty-nine percent had normal ALT and no HCV RNA, compared with none of the controls (p = 0.035). Four patients (22) had had sustained complete responses to interferon, defined as normal ALT levels and no HCV RNA at the end of the 3-mo treatment period and the 18-mo follow-up period. All seven patients with non-A, non-B, non-C hepatitis, treated and untreated, recovered uneventfully from hepatitis. One major finding was that short-term treatment with interferon-α was effective in most patients with acute hepatitis C and led to complete recovery from hepatitis in 39 of the cases. (Hepatology 1994;19:19–22).