Sigma receptors are nonopiate and nonphencyclidine binding sites that are thought to be neuroprotective due to modulation of N-methyl-D-aspartate (NMDA) receptors. Sigma receptor 1 expression has been demonstrated in numerous tissues including brain. Recently, studies using binding assays have demonstrated sigma receptor 1 in neural retina, however these studies did not demonstrate in which retinal cell type(s) sigma receptor 1 was present nor did they establish unequivocally the molecular identity of the receptor. The present study was designed to address these issues. Reverse transcription-polymerase chain reaction (RT-PCR) analysis amplified sigma receptor 1 in neural retina, RPE-choroid complex, and lens isolated from mice. A similar RT-PCR product was amplified also in three cultured cell lines, rat Müller cells, rat ganglion cells and human ARPE-19 cells. In situ hybridization analysis revealed abundant sigma receptor 1 expression in ganglion cells, cells of the inner nuclear layer, inner segments of photoreceptor cells and retinal pigment epithelial (RPE) cells. Immunohistochemical studies detected the sigma receptor 1 protein in retinal ganglion, photoreceptor, RPE cells and surrounding the soma of cells in the inner nuclear layer. These data provide the first cellular localization of sigma receptor 1 in neural retina and establish the molecular identity of sigma receptor 1 in retinal cells. The demonstration that sigma receptor 1 is present in ganglion cells is particularly noteworthy given the well-documented susceptibility of these cells to glutamate toxicity. Our findings suggest that retinal ganglion cells may be amenable to the neuroprotective effects of sigma ligands under conditions of neurotoxicity such as occurs in diabetes.