The authors have investigated the course of herpes simplex type 1 (HSV) keratitis in three different inbred strains of mice infected with four different HSV isolates. Severity of ocular disease and mortality is dependent upon both the virus isolate and the host strain. In particular, the likelihood of progression from self-limited dendritic keratitis to severe necrotizing stromal keratitis varies markedly among the virus-host strain combinations tested. When mice from strains resistant to stromal disease are crossed with mice from strains susceptible to stromal disease, the F1 offspring are resistant, suggesting that the gene(s) controlling resistance is dominant. Corneal stromal keratocytes and embryo fibroblasts from inbred mice differ significantly in their ability to support the replication of HSV in vitro. HSV replicates more efficiently in vitro in keratocytes from mice susceptible to stromal keratitis than it does in keratocytes from mice resistant to stromal keratitis. These findings provide evidence in an animal model for both virus- and host-related mechanisms that determine susceptibility to stromal keratitis.