During HIV+ hepatitis C virus (HCV)+ coinfection CD14brightCD16− monocytes produce soluble immune-activation markers that predict disease progression and poor response to interferon (IFN)-α treatment. We evaluated relationships among immune activation, monocyte phenotype, CD4-memory T cells, and HCV−, cytomegalovirus−, and cytomegalovirus/Epstein-Barr virus/influenza–specific IFN-γ-response before and during IFN-α treatment. Effector-memory and central-memory CD4 T-cell frequencies were lower in HCV+ HIV+ donors than in uninfected donors and correlated negatively with HCV level, CD14brightCD16− monocytes, and plasma sCD14. sCD14 and CD14brightCD16− monocytes negatively correlated with IFN-α–dependent HCV decline. CD4 effector-memory T cells positively associated with cytomegalovirus/Epstein-Barr virus/influenza(CEF)-specific IFN-γ response, while sCD14 negatively associated with both CD4 effector-memory T cells and CEF-specific IFN-γ response. These data support a role for memory-CD4 T cells in HCV containment and link immune activation and CD14brightCD16−-monocyte frequency to the failure of IFN-dependent HCV clearance.