Stimulus-specific changes in levels of corticotropin-releasing factor (CRF) mRNA in inferior olivary neurons were studied in unanesthetized rabbits. The possible functional importance of CRF, a neuropeptide that is expressed in all inferior olivary neurons, in cerebellar synaptic transmission was investigated in a subpopulation of inferior olivary neurons, the caudal dorsal cap. Previous studies have shown that unidirectional, binocular optokinetic stimulation increases the level of discharge in neurons located in one of the caudal dorsal caps of the inferior olive and decreases the level of discharge in neurons in the opposite dorsal cap. We investigated the influence of prolonged (1–144 hr), unidirectional, binocular, optokinetic stimulus on the levels of CRF mRNA in dorsal cap neurons, measured with the technique of hybridization histochemistry. Rabbits were placed at the center of a cylindrical optokinetic drum that rotated at a constant velocity of 5 deg/sec, stimulating one eye in the posterior-to-anterior direction and the contralateral eye in the anterior-to-posterior direction. Posterior- to-anterior stimulation of the left eye evoked increased activity of inferior olivary neurons located in the right caudal dorsal cap. Conversely, anterior-to-posterior stimulation of the right eye evoked decreased activity of neurons in the left caudal dorsal cap. The levels of CRF mRNA in dorsal cap neurons that were activated by prolonged optokinetic stimulation were increased by a factor of 4 to 7 after 48 hr of stimulation and by more than a factor of 10 after 144 hr of optokinetic stimulation. These optokinetically induced increases in CRF mRNA decayed to background levels after 30 hr. Our observations implicate CRF in visual olivocerebellar function and suggest that CRF may play a role in the plastic control of eye movement mediated by the visual olivocerebellar system.