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Tumor necrosis factor alpha (TNF-␣) has been shown to have a protective role in the eyes and brains of herpes simplex virus type 1 (HSV-1)-infected mice. To determine whether overexpression of TNF-␣ affected the course of virus infection following uniocular anterior chamber inoculation, a recombinant of HSV-1 that produces TNF-␣ constitutively (KOSTNF) was constructed. BALB/c mice were injected with the TNF-␣ recombinant, a recombinant containing the pCI plasmid, a recombinant rescue virus, or the parental virus. Flow cytometry and immunohistochemistry were used to identify virus-infected cells and to determine the numbers and types of infiltrating inflammatory cells in the uninjected eyes. Virus titers were determined by plaque assay. There were no differences among the groups in virus titers or the route and timing of virus spread in the injected eyes or in the suprachiasmatic nuclei. However, in the uninjected eyes of KOSTNF-infected mice, TNF-␣ expression was increased and there were more viral antigen-positive cells and immune inflammatory cells. There was earlier microscopic evidence of retinal infection and destruction in these mice, and the titers of virus in the uninjected eyes were significantly increased in KOSTNF-infected mice on day 7 postinfection compared with those of KOSpCI-, KOS6␤rescue-, or KOS6␤-infected mice. The results suggest that instead of moderating infection and reducing virus spread, overexpression of TNF-␣ has deleterious effects due to increased inflammation and virus infection that result in earlier destruction of the retina of the uninoculated eye.