Fifty percent of healthy hepatitis B surface antigen carriers may have histologically proven chronic hepatitis. Our aim was to study the benefit of interferon-alpha in healthy patients. Twenty-nine hepatitis B surface antigen carriers with normal liver enzymes and with serum hepatitis B virus DNA were randomized into two groups: Group I, 14 patients treated with 9 megaunits of interferon alpha-2a thrice weekly for six months, and Group II, 15 control patients. A liver biopsy was obtained from each patient at study initiation. A second biopsy was available in nine treated patients and six controls. During treatment, a significant increase in alanine amino transferase levels was observed in treated patients as compared with the controls (P < 0.05). After treatment, transaminase levels decreased to normal values. No differences between treated and control patients were observed in clearance of hepatitis B virus markers. A significant increase in the total histological activity index between base line and final liver biopsies was observed in treated patients (P < 0.05). It is concluded that interferon alpha treatment may induce a biochemical and histological activation of liver disease. Accordingly, interferon alpha should not be administered to healthy hepatitis B surface antigen carriers, at least with the schedule used in this work.