We examined the effects of doxycycline hyclate on epithelial healing in vivo in the rabbit alkali-burn model. Twelve 2-3-kg Dutch belted rabbits were divided into three groups and received standard bilateral alkali burns (1 N sodium hydroxide for 30 s in an 11-mm circular plastic well). In group 1, two rabbits (four eyes) served as untreated controls. In group 2, five rabbits (10 eyes) received doxycycline hyclate (1.5 mg/kg) orally daily for 14 days. In group 3, five rabbits (10 eyes) received doxycycline hyclate (5 mg/kg) orally daily for 14 days. The epithelial defects were drawn and photographed on alternate days, after fluorescein staining. At conclusion, extracts of the corneas were evaluated for collagenase activity. At 14 days, the mean percentage of epithelial defects results in groups 1-3 were 50.0, 50.7, and 7.1%, respectively. Using the Wilcoxon rank sum test (two tailed), the differences were found to be statistically significant (p = 0.0015). Preliminary data indicated that oral doxycycline administration also decreased the collagenase activity in corneas obtained from these animals. Our preliminary findings indicated that systematically administered doxycycline hyclate, 5 mg/kg/day, promotes corneal reepithelialization in the rabbit alkali-burn model, a result, perhaps, of the drug's ability to inhibit excessive collagenase activity.