Evidence has shown that effects from oxidative stress induced damage of retinal or human retinal pigment epithelial (RPE) cells. Antioxidant supplementation is a plausible strategy to avoid oxidative stress and maintain the function of retina. d-Arg-2,6-dimethyltyrosine-Lys-Phe-NH2 (SS-31) has been used in the treatment of many diseases. In this study, we found that SS-31 attenuated hydrogen peroxide (HO)-induced loss of cell viability, reduced oxidative damage and cell apoptosis in RPE cells. HO-1, Trx-1 and Nrf-2 expression levels significantly increased on pre-treatment with SS-31 compared with the HOgroup. SS-31 inhibited apoptosis through the downregulation of Bax and the upregulation of Bcl-2. Our results suggest that SS-31 had a protective effect against HOtreatment in ARPE-19 cells by enhancing the antioxidative enzymes expression and decreasing apoptosis, which could be considered a promising therapeutic intervention for retinal degeneration.