The morphologic effect of hyperosmolarity, equivalent to that seen in the tear film of patients with keratoconjunctivitis sicca (KCS), on rabbit corneal epithelium in vitro and in vivo was studied. In the in vitro studies, corneal epithelium was grown in explant cultures. Control tissue was cultured in a 307 mOsm/L medium. Epithelium cultured in the 333, 361 and 363 mOsm/L media showed decreased intercellular connections, blunting and loss of microplicae, disruptions in cell membranes and cellular swelling with decreased cytoplasmic density. In in vivo studies, corneas bathed in balanced salt solutions (BSS) concentrated to 330, 360, or 407 mOsm/L showed increased cell desquamation, and the cell changes observed at similar osmolarities in the in vitro studies. The tear film osmolarities observed in KCS are sufficient to cause the corneal epithelial changes seen in patients with this disease.