Athymic (nude) mice have played an important role in defining the function of the immune system and its role in infectious diseases. In the majority of these studies, heterozygous +/nu mice have been used as normal controls for the nu/nu mice, and it has been assumed that +/nu mice have essentially normal immune systems. We have compared the response of +/+, +/nu and nu/nu BALB/c mice following ocular infection with HSV-1 and have found that +/nu mice develop significantly more severe blepharitis, vascularization of the cornea, stromal keratitis and extraocular disease (herpetiform spread) than +/+ BALB/c mice. The extraocular disease was particularly severe in the +/nu mice, suggesting that factors regulating herpetiform spread of the virus are deficient in these mice. Susceptibility to lethal encephalitis did not differ between +/+ and +/nu mice. These results suggest that significant differences exist in the response to ocular HSV infection between +/+ and +/nu mice.