The efficacy and safety of recombinant α-interferon (IFN) therapy for chronic hepatitis C (CHC) was assessed in 57 HIV-infected individuals with CD4+ T cells above 200/mm 3 and compared to the response obtained in 21 HIV-negative patients with CHC. IFN 5 mega⊎ was given three times a week subcutaneously for 3 months. In responding patients, IFN 3 mega⊎ three times a week was additionally administered for 9 months. After 8 months follow-up in HIV-infected patients, 38% (22/57) achieved normal (complete response, CR) alanine aminotransferase (ALT) values. Partial response (PR) was seen in 21% (12/57), and 40% (23/57) did not respond. Patients with CD4+ cells above 500/mm 3 achieved CR in 58% (14/24) of cases compared to 24% (8/33) among those having a lower CD4+ count (P<0.01). Females attained CR in 60% (9/15) of cases, and men in only 30.9% (13/42) (P<0.01). No serious side effects or opportunistic infections were observed during the study period. However, three (5.2%) patients showed a dramatic fall in total CD4+ T cell count after beginning IFN therapy.Among 21 HIV-negative patients, after 8 months follow-up, CR was achieved in 10 (47%), PR in four (19%), and seven (33%) did not respond. We concluded that IFN therapy seems to be well tolerated and useful in HIV-infected patients suffering CHC. The rate of CR was not significantly different compared to that observed in HIV-negative patients (38% vs. 47%), relative risk (RR) = 0.67 (0.19–2.37). However, in HIV-positive patients, a lack of response to IFN therapy was particularly associated with a CD4+ cell count lower than 500/mm 3 (only 24% achieved CR) compared to the response obtained in patients with CD4+ count above 500/mm 3 (CR was seen in 58%) (P<0.01). The effect of IFN therapy on CD4+ T cells needs to be clarified in these patients.