Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) co-infected patients have lower rates of sustained viral response (SVR) to treatment than HCV mono-infected patients. A rapid viral response (RVR) with negative HCV-RNA at week 4 predicts SVR in most patients. We evaluated the RVR for the prediction of SVR in mono-and co-infected patients, and the effect caused by the selection of mono-infected controls on SVR rates. Co-infected (n = 13) and mono-infected naïve patients (n = 100) with HCV genotype 2/3 were treated with 135 microg pegylated interferon alpha-2a weekly and weight-based ribavirin daily for 24 weeks. For each co-infected patient, 2 mono-infected controls matched for genotype, baseline viral load, and age, were chosen. RVR was achieved in 6/13 (46%) co-infected, 16/26 (62%) matched controls, and 69/98 (70%) mono-infected patients. All co-infected, 14/16 (88%) matched controls, and 66/69 (96%) mono-infected patients with RVR achieved SVR. In total SVR was reached by 10/13 (77%) co-infected patients and 20/26 (77%) matched controls, somewhat lower than the 86/100 (86%) mono-infected patients (not significant). The ability of RVR to predict SVR was high both in co-infected and mono-infected patients with genotypes 2 and 3 chronic HCV, and the results indicate that co-infected patients with well controlled HIV (with CD4 T-cell counts above 300/microl) can be offered the same treatment as mono-infected patients.