PURPOSE. To examine the potential harmful effects on corneal structure, innervation, and sensitivity of a spray containing the neurotoxin capsaicin (oleoresin capsicum, OC). METHODS. Ten police officers who volunteered for the study were exposed to OC. Clinical signs were assessed. Corneal sensitivity was measured using a Cochet-Bonnet or a noncontact esthesiometer that provides separate measurements of mechanical, chemical, and thermal sensitivity. Tear fluid nerve growth factor (NGF) was measured. Corneal cell layers and subbasal nerves were examined by in vivo confocal microscopy. The subjects were examined before application and 30 minutes, 1 day, 1 week, and 1 month after OC exposure. RESULTS. OC spray produced occasional areas of focal epithelial cell damage that healed within 1 day. Each eye showed conjunctival hyperemia and in two subjects, mild chemosis. All except one eye had unchanged best corrected visual acuity (BCVA). A transient decrease (day 1) of mechanical sensitivity was observed with the Cochet-Bonnet esthesiometer. With the gas esthesiometer, mechanical sensitivity remained below normal values for 7 days. Chemical sensitivity to CO 2 was high for as much as 1 day and decreased below normal 1 week later, whereas sensitivity to cold was unaffected. Two subjects had measurable tear NGF that increased after exposure. Basal epithelial cell morphology suggested temporary corneal epithelial swelling, whereas keratocytes, endothelial cells, and subbasal nerves remained unchanged. CONCLUSIONS. Although OC causes immediate changes in mechanical and chemical sensitivity that may persist for a week, a single exposure to OC appears harmless to corneal tissues. The changes are possibly associated with damage of corneal nerve terminals of mainly unmyelinated polymodal nociceptor fibers. (Invest Ophthalmol Vis Sci. 2000;41:2138 -2147 T he cornea receives sensory innervation from primary sensory neurons located in the trigeminal ganglion 6 -9 Corneal nerve fibers exhibit immunoreactivity for a great variety of neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), 10 -19 as well as classic neurotransmitters, presumably associated with autonomic nerve fibers. 9,20 -22 Functionally, corneal nerve fibers have been classified as mechanosensory units, activated only by mechanical stimulation, polymodal units, responding also to chemical substance and to heat, and cold-sensitive units, that are excited by low temperatures (see Reference 23 for review). Capsaicin (8-methyl-vanilyl-6-nonenamide), the pungent component of chili peppers, has been shown to induce intense pain in humans and pseudoaffective pain reactions in animals when applied to the skin and the front of the eye, as well as neurogenic inflammation due to the release of neuropeptides contained in nerve terminals. 24 -26 Capsaicin's effects are associated with acute stimulation of primary sensory nerve endings, 39 Capsaicin treatment in adult animals causes less prominent but still detectable alterations of sensory innervation. In vitro and in vivo studies show that nerve growth factor (NGF) reverses the decrease of transmitter content and restores the peripheral function of primary afferent neurons impaired by capsaicin treatment