T cell proliferation is a pivotal to an effective immune response. Cyclin-dependent kinase (cdk) inhibitor, p27(kip1) is degraded to initiate T cell expansion. In this study, we show that although the expression of p27(kip1) protein was down-regulated, that of p21(cip1), another cdk inhibitor, was up-regulated in CD8+ T cells following in vitro stimulation. Ex vivo gB antigen-stimulation following HSV immunization increased p21(cip1) positive cells that co-expressed IFN-γ. Moreover, p21(cip1) was co-expressed with IFN-γ in E7 antigen-stimulated CD8+ T cells, whereas p27kip1 was not. Our findings imply a role of p21(cip1) proteins in antigen-induced effector CD8+ T cells differentiation in vivo.