Mathematical modeling of the biological effect of interferon on virus decay permits the quantification of the efficacy (epsilon) of blocking virion production in different patient populations. The viral dynamic and immunologic responses of hepatitis C virus (HCV) infection to daily interferon therapy were characterized in twelve patients co-infected with human immunodeficiency virus (HIV). Three out of the twelve patients (25%) achieved an early viral response, a two-log reduction in HCV RNA by week 12. The mean epsilon of IFN-alpha in blocking HCV and HIV production were 72% and 74%, respectively. For HCV epsilon was highest (97%) in the one patient who had a sustained viral response, while it was reduced in the other two patients (68% and 77%). Baseline HCV RNA and the number of CD3+CD56+16+ cells were inversely related (r = -0.89, p = 0.03), and baseline HCV-specific immune responses were significantly higher in the three patients with 2-log viral load reductions. These data suggest that: 1) interferon efficacy at blocking virion production is correlated with treatment outcome in HIV/HCV co-infected patients, 2) that immunodeficient patients can respond to standard IFN-alpha, 3) that both innate and adaptive immune responses may be important determinants of HCV RNA decline in response to interferon.