This prospective randomized study investigates the possible toxic effects of interferon (IFN) (alpha 2A on the mouse cochlea. Thirty-six albino Swiss mice that were randomly assigned to 3 groups underwent baseline auditory brain stem response testing bilaterally to objectively assess baseline hearing levels. The first group received a single dose of 50,000 units, and the second group received 100,000 units of IFN-alpha 2A intraperitoneally, whereas the third group was given no medication. Repeat auditory brain stem response testing revealed a significant rise in mean baseline peak equivalent sound pressure level thresholds in the groups that received IFN (P < 0.001), Histologicallly, the cochleae of mice that received IFN had a decreased number of fibroblasts in the spiral limbus, as well as prominent cytoplasmic vacuolation of these cells, compared with control animals. Loss of hair cells was not observed. It is possible that reversible biochemical and metabolic changes in the cochlea, rather than morphologic abnormalities, manifest IFN ototoxicity.