Low response rates and concerns about safety have limited the implementation of treatment for chronic hepatitis C (CHC) in patients with HIV infection. The efficacy and safety of pegylated interferon (peg-IFN) plus ribavirin in HIV-infected patients with CHC were evaluated in a prospective, open-label, multicenter study. Sixty patients with persistently high transaminases, positive HCV-RNA, CD4 count ≥300 cells/µl, and HIVRNA <10,000 copies/ml were included. Patients were given peg-IFN 80-150 µg/week plus ribavirin 800-1200 mg/day. Treatment was scheduled for 24 weeks for genotypes 2/3 and 48 weeks for genotypes 1/4. In an intent- to-treat analysis, 16 (26.7%) patients achieved a sustained virological response (SVR). Twenty patients (33.3%) discontinued treatment prematurely, but only in 10 (16.6%) was discontinuation due to adverse events. Negative predictive values for SVR on the basis of HCV-RNA decline between baseline and week 4 were 100% for 1- and 2-log10 fall, and positive predictive values were 40% and 58.3% for 1- and 2-log10 fall, respectively. CD4 fell by a median of 216 cells during treatment, but no HIV-associated complications occurred. In conclusion, treatment with peg-IFN alfa-2b plus ribavirin is safe and clears RNA-HCV in about one-quarter of HIV-infected patients with CHC. Efforts should be focused on optimizing management of side effects and counseling to improve adherence and to keep patients on treatment. Assessment of HCV-RNA at week 4 may help guide early therapeutic decision making.