This study investigates the role of interleukin-10 (IL-10) in the resolution of chronic viral infections. The authors found that IL-10 production is significantly increased in mice persistently infected with lymphocytic choriomeningitis virus (LCMV). In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody led to rapid resolution of the persistent infection by reducing IL-10 secretion and enhancing interferon-γ production by antiviral CD8+ T cells. CD8α+ dendritic cells (DCs) were found to be depleted early in persistently infected mice, while CD8α− DCs supported IL-10 production and dampened antiviral T cell responses. Therapeutic IL-10R blockade disrupted 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. The results highlight the importance of IL-10 in maintaining chronic viral infections and suggest that IL-10R blockade may be a potential therapeutic strategy for chronic viral infections.This study investigates the role of interleukin-10 (IL-10) in the resolution of chronic viral infections. The authors found that IL-10 production is significantly increased in mice persistently infected with lymphocytic choriomeningitis virus (LCMV). In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody led to rapid resolution of the persistent infection by reducing IL-10 secretion and enhancing interferon-γ production by antiviral CD8+ T cells. CD8α+ dendritic cells (DCs) were found to be depleted early in persistently infected mice, while CD8α− DCs supported IL-10 production and dampened antiviral T cell responses. Therapeutic IL-10R blockade disrupted 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. The results highlight the importance of IL-10 in maintaining chronic viral infections and suggest that IL-10R blockade may be a potential therapeutic strategy for chronic viral infections.