Herpes simplex virus type 1 (HSV-1) infection of the eye leads to the retrograde spread of the virus from the eye to the trigeminal ganglion resulting in the infiltration of leukocytes and production of inflammatory cytokines and chemokines including CXCL9 and CXCL10. The present study investigated the role of the receptor for CXCL9 and CXCL10 in the host response to HSV-1 infection using mice deficient in CXCR3 expression (CXCR3-/-). Although wild type C57BL/6 and CXCR3-/- mice cleared the virus, HSV-1 titers remained elevated in the ganglion and brain stem of CXCR3-/- mice day 7 post infection. Coinciding with the increase in virus titer, CCL5, CXCL9, CXCL10 and IFN-gamma protein levels were enhanced in the trigeminal ganglion and/or brain stem of the CXCR3-/- mice associated with a 2-fold increase in the percentage of CD3+CD8+ T lymphocytes in the trigeminal ganglion. However, the survival rate of CXCR3-/- mice was significantly enhanced above the wild type controls associated with an increase in brain IL-6 content. Collectively, the results indicate the absence of CXCR3 is associated with a transient increase in virus burden in the nervous system and an elevated protective immune response.