Following direct antigen challenge to the endolymphatic sac (sac), the relation of caloric test results and spontaneous nystagmus to the histological changes of the sensory epithelium of the vestibular organ and perilymph antibody levels was investigated in the guinea pig. In a secondary keyhole limpet hemocyanin (KLH) challenge to the sac, irritative nystagmus was followed by paralytic nystagmus and a suppression of caloric reaction. These findings correlated well with the degree of degeneration of the sensory epithelium of the vestibular organ and the levels of perilymph antibody. On the other hand, neither phosphate-buffered saline inoculation nor primary KLH challenge to the sac nor a secondary KLH challenge to the intradural space resulted in a disturbance of the vestibular function. These results suggest that the immune response of the sac may possibly be an important key to the pathogenesis of Ménière’s dise