Hearing impairment is a worldwide health problem. Employing semi-quantitative immunological detection methods, we found that the apoptosis inhibitor protein Birc5 is expressed in cell types critical for hearing perception. In the guinea pig model, moderate noise exposure causing only a temporary mean hearing impairment of 33 dB significantly enhanced Birc5 expression in the spiral ligament, nerve fibers and the organ of Corti. In contrast, intratympanic gentamicin injection inducing permanent cell damage and mean hearing loss of 24 dB correlated with a significant Birc5 downregulation in the ligament, nerve fibers and the organ of Corti. The cytoprotective activity of the guinea pig and human Birc5 protein was confirmed by cloning of the gene and by subsequent ectopic expression and challenging studies against the ototoxin gentamicin in epithelial and auditory cell models. As the mammalian cochlea is unable to regenerate upon damage, these data suggest that modulation of Birc5 expression may represent a novel physiological mechanism to protect the inner ear against stress-induced cell damage. Hence, the targeted modulation of Birc5 levels may lead to novel otoprotective therapeutic strategies.