Potentially blinding eye infections can occur after vaccination for Smallpox. Very little is known about the pathologic mechanisms that are involved and the information that is available was generated using rabbit models. The lack of immunological reagents for rabbits makes such studies difficult. We have characterized a mouse model of vaccinia virus ocular disease using C57BL/6 mice and strain WR and show that both CD4+ and CD8+ T-cell subsets play a role in the blinding eye disease and controlling virus replication. Based on these results vaccinia virus keratitis is significantly different from Herpes simplex virus keratitis and further studies using this model should generate novel insights into immunopathological responses to viral ocular infection.