The effects of the interaction between kanamycin (KAN) and ethacrynic acid (EA) on the ultrastructure of the guinea pig cochlea were studied 3, 4, 6, and 24 hours following administration of EA (40 mg/kg) to animals pretreated 2 h earlier with KAN (400 mg/kg). Appropriate saline (SAL) controls were included giving 4 treatments: KAN/EA, KAN/SAL, SAL/EA and SAL/SAL. The outer hair cells of the organ of Corti showed nuclear and plasma membrane changes at 3 h and were completely destroyed at 24 h. The inner hair cells were unaffected. Severe swelling was seen in the stria vascularis of both KAN/EA and SAL/EA animals at 3 h and was gone by 24 h. KAN/EA had a greater effect on the stria than had SAL/EA. These results were consistent with the time course of the effect of the drugs on the a.c. and d.c. endocochlear potentials. KAN concentrations in perilymph were unaffected by treatment with EA.