Calpains, a family of calcium activated proteases, promote the breakdown of cellular proteins, kinases, phosphatases and transcription factors. Calpain inhibitors attenuate some neurodegenerative processes in certain cell types. Here we show that leupeptin, a potent calpain inhibitor, protects the sensory hair cells in the inner ear from acoustic overstimulation (48 h, 100 or 105 dB SPL, octave band noise at 4 kHz). Acoustic overstimulation caused a significant increase in calpain immunolabeling in the sensory epithelium suggesting a possible role in noise-induced cochlear degeneration. Infusion of leupeptin into the inner ear significantly reduced the amount of sensory cell loss from acoustic overstimulation. However, leupeptin did not protect against hair cell loss from the ototoxic drug, carboplatin.