IL-10 determines viral clearance or persistence in vivo Persistent viral infections are a major health concern. One obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral T cells. Although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of T-cell activity and promote viral persistence are unknown. Herein, we document that persistent viral infection in mice results in a significant upregulation of interleukin (IL)-10 by antigen-presenting cells, leading to impaired T-cell responses. Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses. Therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated viral infection. Thus, we identify a single molecule that directly induces immunosuppression leading to viral persistence and demonstrate that a therapy to neutralize IL-10 results in T-cell recovery and the prevention of viral persistence. Effective T-cell responses are crucial for the clearance of viral infection. In some instances, however, the immune response is unable to control viral replication, thereby allowing the virus to persist. Concomitant with the transition to persistence, virus-specific CD4+ and CD8+ T cells either are physically deleted or become functionally unresponsive, losing activity and the ability to produce key antiviral and immune stimulatory cytokines. The loss of T-cell function occurs during persistent infection by a diverse range of viruses, including HIV and hepatitis B (HBV) and C (HCV) virus infections of humans and lymphocytic choriomeningitis virus (LCMV) infection of rodents, indicating that conserved mechanisms of immunosuppression may downregulate T-cell activity. A recent report demonstrated that Programmed Death-1 (PD-1) is critical for sustaining suppression of CD8+ T cells during persistent infection. However, the mechanism(s) that initially induces immunosuppression and leads to the loss of T-cell cytolytic and stimulatory functions is unknown. Here we elucidate a molecule that initiates T-cell inactivation and, consequently, viral persistence. Increased IL-10 production early during persistent viral infection To determine the mechanism(s) by which viruses induce immunosuppression, we used the LCMV model. Infection of mice with the LCMV variant Armstrong (Arm) induces a robust T-cell response that results in viral clearance within 8–10 d. Infection with the LCMV variant Clone 13 (Cl 13), a virus initially derived from LCMV-Arm, generates a persistent infection owing to a single amino acid change in its glycoprotein that enables high-affinity binding to dendritic cells (DCs), accompanied by a marked depletion and inactivation of virus-specific T cells. Arm and Cl 13 share identicalIL-10 determines viral clearance or persistence in vivo Persistent viral infections are a major health concern. One obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral T cells. Although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of T-cell activity and promote viral persistence are unknown. Herein, we document that persistent viral infection in mice results in a significant upregulation of interleukin (IL)-10 by antigen-presenting cells, leading to impaired T-cell responses. Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses. Therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated viral infection. Thus, we identify a single molecule that directly induces immunosuppression leading to viral persistence and demonstrate that a therapy to neutralize IL-10 results in T-cell recovery and the prevention of viral persistence. Effective T-cell responses are crucial for the clearance of viral infection. In some instances, however, the immune response is unable to control viral replication, thereby allowing the virus to persist. Concomitant with the transition to persistence, virus-specific CD4+ and CD8+ T cells either are physically deleted or become functionally unresponsive, losing activity and the ability to produce key antiviral and immune stimulatory cytokines. The loss of T-cell function occurs during persistent infection by a diverse range of viruses, including HIV and hepatitis B (HBV) and C (HCV) virus infections of humans and lymphocytic choriomeningitis virus (LCMV) infection of rodents, indicating that conserved mechanisms of immunosuppression may downregulate T-cell activity. A recent report demonstrated that Programmed Death-1 (PD-1) is critical for sustaining suppression of CD8+ T cells during persistent infection. However, the mechanism(s) that initially induces immunosuppression and leads to the loss of T-cell cytolytic and stimulatory functions is unknown. Here we elucidate a molecule that initiates T-cell inactivation and, consequently, viral persistence. Increased IL-10 production early during persistent viral infection To determine the mechanism(s) by which viruses induce immunosuppression, we used the LCMV model. Infection of mice with the LCMV variant Armstrong (Arm) induces a robust T-cell response that results in viral clearance within 8–10 d. Infection with the LCMV variant Clone 13 (Cl 13), a virus initially derived from LCMV-Arm, generates a persistent infection owing to a single amino acid change in its glycoprotein that enables high-affinity binding to dendritic cells (DCs), accompanied by a marked depletion and inactivation of virus-specific T cells. Arm and Cl 13 share identical