• A model of herpes simplex interstitial keratitis was developed in rabbits sensitized with live herpes simplex virus (HSV) type 2 and challenged intrastromally with live virus. This model was used to evaluate the effects of subconjunctival medroxyprogesterone acetate on the course of the disease and on collagenase levels in the treated corneas. Whether treated prophylactically or therapeutically, the medroxyprogesterone-treated groups had substantially less stromal infiltration and neovascularization than the controls. The clinical effects corresponded with a marked reduction in the polymorphonuclear leukocyte infiltrate histologically, and the suppression of latent and active collagenase activity in the treated corneas cultured in vitro. However, epithelial disease was exacerbated in prophylactically treated animals. Medroxyprogesterone appears to be useful in the treatment of herpetic interstitial keratitis as an anti-inflammatory agent as well as an inhibitor of collagenase production but, like the corticosteroids, it can exacerbate epithelial disease.