The effects of isotonic saline on corneal penetration, thickness, and injury, as well as lacrimal secretion in a rat model of dry eye were investigated, in comparison with distilled water. Male Sprague-Dawley rats received intraperitoneal administration of atropine sulfate (20 mg/kg) and their eyes were exposed to dry (relative humidity 25-35%) air flow (2.4 m/sec), under Zoletil anesthesia, for 5 hr to induce dry eye. During the period of dry eye induction, distilled water or isotonic saline (5 μl) was instillated onto the cornea every 30 min. Corneal penetration was measured through fluorescein dye quantification, and corneal thickness and injury were examined under a microscope. Lacrimal (tear) secretion and mucin-like glyocoprotein excretion from goblet cells were measured using the Schirmer test and microscopy, respectively. In dry eye rats treated with distilled water, corneal thickness, tear secretion, and mucin-like glycoprotein excretion were decreased to 74.0%, 74.1%, and 46.3% of normal levels, respectively, resulting in marked corneal injury and a significant increase in corneal penetration. In comparison, treatment with isotonic saline resulted in recovery of lacrimal secretion, in spite of a slight improvement of mucin-like glycoprotein excretion, and thereby prevented corneal penetration of fluorescein by 10%. The results indicate that repeated instillation of isotonic saline could provide slightly greater protection from corneal injury, compared with distilled water by facilitating lacrimal secretion, in addition to relief of inconvenience and pain.