A defining feature of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses immune responses by modulating T cells and antigen-presenting cells. This study shows that IL-10 production is significantly increased in mice infected with lymphocytic choriomeningitis virus (LCMV). In vivo blockade of the IL-10 receptor with a neutralizing antibody rapidly resolved the persistent infection. IL-10 secretion was reduced, and interferon gamma (IFN-γ) production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8α+ dendritic cells (DCs) declined early after infection, whereas CD8α− DCs supported IL-10 production and subsequent suppression of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10-mediated immune suppression, preventing IL-10 priming by CD8α− DCs and enhancing antiviral responses, thereby resolving infection without causing immunopathology. IL-10 inhibits a broad spectrum of cellular immune responses. It suppresses the function of antigen-presenting cells (APCs) and T cells by inhibiting proinflammatory cytokine production, co-stimulation, MHC class II expression, and chemokine secretion. IL-10 has been associated with immunopathology in various immune-mediated and inflammatory diseases. For example, treatment with a combination of anti-IL-10R monoclonal antibody and Toll-like receptor 9 (TLR9) ligands had potent therapeutic antitumor effects, indicating a role for IL-10 in the pathogenesis of cancer. Viruses use various strategies to avoid recognition by the host immune system. The active induction of immune suppression is one mechanism by which viruses escape clearance and establish a persistent infection. In humans, chronic viral infections affect millions of people worldwide. Elevated levels of IL-10 production have been associated with persistent infection by hepatitis C virus (HCV), HIV, and Epstein-Barr virus. IL-10 production by CD8+ T cells in HCV-infected individuals suppresses the proliferative responses of liver-derived lymphocytes in an HCV-specific and IL-10-dependent manner. Both CD4+ and CD8+ T cells have been shown to express high levels of IL-10 in HIV-infected individuals. To gain further insight into the role of IL-10 in the establishment and maintenance of persistent viral infections, we investigated whether this cytokine is involved in the persistence of LCMV infection in its natural host, the mouse. LCMV is an arena virus that can cause either acute or persistent infection in vivo depending on the strain, route of infection, and dose of virus. Although adult mice infected with LCMV Armstrong rapidlyA defining feature of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses immune responses by modulating T cells and antigen-presenting cells. This study shows that IL-10 production is significantly increased in mice infected with lymphocytic choriomeningitis virus (LCMV). In vivo blockade of the IL-10 receptor with a neutralizing antibody rapidly resolved the persistent infection. IL-10 secretion was reduced, and interferon gamma (IFN-γ) production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8α+ dendritic cells (DCs) declined early after infection, whereas CD8α− DCs supported IL-10 production and subsequent suppression of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10-mediated immune suppression, preventing IL-10 priming by CD8α− DCs and enhancing antiviral responses, thereby resolving infection without causing immunopathology. IL-10 inhibits a broad spectrum of cellular immune responses. It suppresses the function of antigen-presenting cells (APCs) and T cells by inhibiting proinflammatory cytokine production, co-stimulation, MHC class II expression, and chemokine secretion. IL-10 has been associated with immunopathology in various immune-mediated and inflammatory diseases. For example, treatment with a combination of anti-IL-10R monoclonal antibody and Toll-like receptor 9 (TLR9) ligands had potent therapeutic antitumor effects, indicating a role for IL-10 in the pathogenesis of cancer. Viruses use various strategies to avoid recognition by the host immune system. The active induction of immune suppression is one mechanism by which viruses escape clearance and establish a persistent infection. In humans, chronic viral infections affect millions of people worldwide. Elevated levels of IL-10 production have been associated with persistent infection by hepatitis C virus (HCV), HIV, and Epstein-Barr virus. IL-10 production by CD8+ T cells in HCV-infected individuals suppresses the proliferative responses of liver-derived lymphocytes in an HCV-specific and IL-10-dependent manner. Both CD4+ and CD8+ T cells have been shown to express high levels of IL-10 in HIV-infected individuals. To gain further insight into the role of IL-10 in the establishment and maintenance of persistent viral infections, we investigated whether this cytokine is involved in the persistence of LCMV infection in its natural host, the mouse. LCMV is an arena virus that can cause either acute or persistent infection in vivo depending on the strain, route of infection, and dose of virus. Although adult mice infected with LCMV Armstrong rapidly