Disease progression of human immunodeficiency virus type 1 (HIV-1) is associated with immune activation. Activation indices are higher during coinfection of hepatitis C virus (HCV) and HIV. The effect of immune activation on interferon α (IFN-α) therapy response is unknown. We evaluated soluble CD14 (sCD14) and natural killer (NK)-cell subsets at baseline, and during pegIFN-α2a/ribavirin therapy in HCV-HIV coinfection. The sCD14 level increased during therapy. Baseline sCD14 positively correlated with baseline HCV level and CD16(+)56(-) NK-cell frequency, and both sCD14 and CD16(+)56(-) NK cells correlated negatively with magnitude of HCV decline. IL28B genotype was associated with therapy response but not sCD14 or CD16(+)56(-) NK frequency. Markers of innate immune activation predict poor host response to IFN-α-based HCV therapy during HCV-HIV coinfection.