Abstract Chemokine-mediated T cell migration is essential to an optimal immune response. The p110γ isoform of PI3K is activated by G protein-coupled receptors and regulates neutrophil and macrophage chemotaxis. We used p110γ-deficient mice to examine the role of p110γ in CD8 T cell migration and activation in response to viral challenge. Naive CD8 T cell migration in response to CCL21 in vitro and trafficking into secondary lymphoid organs in vivo was unaffected by the loss of p110γ. Furthermore, loss of p110γ did not affect CD8 T cell proliferation and effector cell differentiation in vitro in response to anti-CD3 stimulation or in vivo in response to vaccinia virus (VV) challenge. However, there was reduced migration of p110γ knockout (p110γ−/−) CD8 effector T cells into the peritoneum following i.p. challenge with VV. The role of p110γ in CD8 effector T cell migration was intrinsic to T cells, as p110γ−/− CD8 effector T cells exhibited impaired migration into the inflamed peritoneum following secondary transfer into wild-type recipients. In addition, p110γ−/− CD8 effector T cells exhibited impaired migration in vitro in response to inflammatory chemoattractants. Although wild-type mice efficiently cleared VV at high viral doses, infection of p110γ knockout mice resulted in visible illness and death less than a week after infection. Thus, p110γ is dispensable for constitutive migration of naive CD8 T cells and subsequent activation and differentiation into effector CD8 T cells, but plays a central role in the migration of effector CD8 T cells into inflammatory sites.