The effects of primary and secondary inner ear immune responses were investigated in the guinea pig. Subjects were immunized with keyhole limpet hemocyanin (KLH). Serum and perilymph anti-KLH titers, cochlear microphonic (CM) and VIII nerve N1 compound action potential (AP) thresholds, and cochlear morphology were examined at 2 or 4 weeks post-inner ear KLH inoculation. Primary inner ear immunized subjects developed serum and perilymph anti-KLH titers, exhibited minimal cochlear histopathology and showed only small changes in CM and AP thresholds at 2 or 4 weeks post-inner ear inoculation. Secondary immune response animals, those which were systemically immunized with KLH prior to inner ear challenge, showed significant serum and perilymph anti-KLH titers, and normal CM and AP thresholds at the time of inner ear challenge. At 2 or 4 weeks following inner ear challenge, secondary immunized animals showed very significant increases in CM and AP thresholds, and marked cochlear histopathology. We conclude that secondary inner ear challenge results in significant cochlear pathophysiology, while primary inner ear immunization does not.