AbstractRetinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal disorders involving the progressive dysfunction of photoreceptors and the retinal pigment epithelium, for which there is currently no treatment. The rd6 mouse is a natural model of autosomal recessive retinal degeneration. Given the known contributions of oxidative stress caused by reactive oxygen species (ROS) and selective inhibition of potent ROS peroxynitrite and OH·by H₂ gas we have previously demonstrated, we hypothesized that ingestion of H₂ water may delay the progression of photoreceptor death in rd6 mice. H₂ mice showed significantly higher retinal thickness as compared to controls on optical coherence tomography. Histopathological and morphometric analyses revealed higher thickness of the outer nuclear layer for H₂ mice than controls, as well as higher counts of opsin red/green-positive cells. RNA sequencing (RNA-seq) analysis of differentially expressed genes in the H₂ group versus control group revealed 1996 genes with significantly different expressions. Gene and pathway ontology analysis showed substantial upregulation of genes responsible for phototransduction in H₂ mice. Our results show that drinking water high in H₂ (1.2–1.6 ppm) had neuroprotective effects and inhibited photoreceptor death in mice, and suggest the potential of H₂ for the treatment of RP.