Exposure to intense sound can damage the mechanosensors of the inner ear and their afferent innervation. These neurosensory elements are innervated by a sound-activated feedback pathway, the olivocochlear efferent system. One major component of this system is cholinergic, and known cholinergic effects are mediated by the alpha9/alpha10 nicotinic acetylcholine receptor (nAChR) complex. Here, we show that overexpression of alpha9 nAChR in the outer hair cells of bacterial artificial chromosome transgenic mice significantly reduces acoustic injury from exposures causing either temporary or permanent damage, without changing pre-exposure cochlear sensitivity to low- or moderate-level sound. These data demonstrate that efferent protection is mediated via the alpha9 nAChR in the outer hair cells and provide direct evidence for a protective role, in vivo, of a member of the nAChR family.