We previously reported that the lack of serglycin proteoglycan affects secretory granule morphology and granzyme B (GrB) storage in in vitro generated CTLs. In this study, the role of serglycin during viral infection was studied by infecting wild-type (wt) mice and serglycin-deficient (SG-/-) mice with lymphocytic choriomeningitis virus (LCMV). Wt and SG/ mice cleared 103 PFU of highly invasive LCMV with the same kinetics, and the CD8+ T lymphocytes from wt and SG-/- animals did not differ in GrB, perforin, IFN-γ, or TNF-α content. However, when a less invasive LCMV strain was used, SG-/- GrB+ CD8+ T cells contained 30% less GrB than wt GrB+ CD8+ T cells. Interestingly, the contraction of the antiviral CD8+ T cell response to highly invasive LCMV was markedly delayed in SG-/- mice, and a delayed contraction of the virus-specific CD8+ T cell response was also seen after infection with vesicular stomatitis virus. BrdU labeling of cells in vivo revealed that the delayed contraction was associated with sustained proliferation of Ag-specific CD8+ T cells in SG-/- mice. Moreover, wt LCMV-specific CD8+ T cells from TCR318 transgenic mice expanded much more extensively in virus-infected SG-/- mice than in matched wt mice, indicating that the delayed contraction represents a T cell extrinsic phenomenon. In summary, the present report points to a novel, previously unrecognized role for serglycin proteoglycan in regulating the kinetics of antiviral CD8+ T cell responses.