Outer hair cells (OHCs) are responsible for the amplification of sound, and the death of these cells leads to hearing loss. Although the mechanisms for sound amplification and OHC death have been well investigated, the effects on the cochlea after OHC death are poorly understood. To study the consequences of OHC death, we established an OHC knockout system using a novel mouse model, Prestin-hDTR, which uses the prestin promoter to express the human diphtheria toxin (DT) receptor gene (hDTR). Administration of DT to adult Prestin-hDTR mice results in the depletion of almost all OHCs without significant damage to other cochlear and vestibular cells, suggesting that this system is an effective tool for the analysis of how other cells in the cochlea and vestibula are affected after OHC death. To evaluate the changes in the cochlea after OHC death, we performed differential gene expression analysis between the untreated and DT-treated groups of wild-type and Prestin-hDTR mice. This analysis revealed that genes associated with inflammatory/immune responses were significantly upregulated. Moreover, we found that several genes linked to hearing loss were strongly downregulated by OHC death. Together, these results suggest that this OHC knockout system is a useful tool to identify biomarkers associated with OHC death.