Megalin, the largest member of the low-density lipoprotein receptor-related protein family, functions as an endocytic receptor for a variety of essential lipophilic metabolites, including the steroid hormone estrogen. In the cochlea, megalin is strongly expressed within the marginal cells of the stria vascularis, and previous studies demonstrated that -estrogen receptors are also expressed in megalin-expressing marginal cells. In the present study, we demonstrate that homozygous megalin mutant mice exhibit profound hearing loss at 3 months of age associated with features of presbycusis, enrichment of lipofuscin granules, and a reduced number of microvilli in marginal cells of the stria vascularis. FITC-labeled -estrogen is taken up into the strial marginal cells; however, in megalin-deficient mice the uptake of FITC-labeled -estrogen is reduced. This highlights -estrogen as a possible carrier-bound candidate ligand for megalin and supports the concept that estrogen may function via megalin within the inner ear. A crucial role of megalin in hearing should be considered and the megalin/estrogen interaction needs to be discussed in the context of early presbycusis in estrogen-deficient humans and mice.—König, O., Rüttiger, L., Müller, M., Zimmermann, U., Erdmann, B., Kalbacher, H., Gross, M., Knipper, M. Estrogen and the inner ear: megalin knockout mice suffer progressive hearing loss.