The β-herpesvirus CMV induces a substantial and progressive expansion of virus-specific memory CD8 T cells, which protect the host against viral reactivation from latency. In this paper, we report that this expansion, or “inflation,” of memory T cells is amplified dramatically during mouse CMV infection of IL-10 knockout (IL-10−/−) mice. T cells from IL-10−/− mice were oligoclonal, exhibited a highly activated phenotype, expressed antiviral cytokines, and degranulated in response to cognate Ag encounter ex vivo. Moreover, latent viral load was reduced in IL-10−/− mice. Importantly, these results were recapitulated by IL-10R blockade during chronic/latent infection of wild-type mice. These data demonstrate that regulatory immune mechanisms can influence CMV-specific T cell memory and suggest a possible rationale for the acquisition of functional IL-10 orthologs by herpesviruses.