To define factors that protect the eye from Staphylococcus aureus keratitis and limit tissue damage once keratitis occurs. Rabbit tears were analyzed for bactericidal and phospholipase A 2 (PLA 2 ) activities on S. aureus. Inhibition by spermidine of PLA 2 anti-staphylococcal activity in tears was tested in vitro and in vivo. Rabbits immunized with heat-inactivated alpha-toxin were challenged with intrastromal injection of S. aureus. Arachidonic acid was cleaved from S. aureus by purified PLA 2 or rabbit tears. Spermidine inhibited these reactions in vitro and facilitated keratitis in vivo. PLA 2 activity decreased with advanced age and shortly following sleep, but increased with keratitis. Antibody to alpha-toxin significantly reduced corneal damage and epithelial cell sloughing during keratitis. PLA 2 is a major host-defense component of rabbit tears. Alpha-toxin is a major mediator of corneal damage, and antibody to alpha-toxin reduces pathologic changes during keratitis.