The effect of prior corneal herpes simplex infection with its resultant corneal hypesthesia on the irritative response of the rabbit eye to topical nitrogen mustard was examined. The miosis and the breakdown of the blood-aqueous barrier that follow the application of topical nitrogen mustard were diminished in eyes infected 3 wk previously with herpes simplex virus. Nonspecific corneal scarring did not affect the response. An axon reflex requiring intact sensory innervation may mediate the response to nitrogen mustard. Pretreatment of normal (noninfected) rabbits with systemic H1 and H2 antihistamines, topical scopolamine hydrobromide or topical and systemic corticosteroids was ineffective in blocking the miosis or increased protein in the aqueous humor following topical nitrogen mustard.