Oxidative stress and subsequent chronic inflammation result in dysfunction of the retinal pigment epithelium (RPE) and represent therapeutic targets in the context of age-related macular degeneration (AMD). However, molecular mechanisms that linked oxidative stress and inflammation still unclear. As an important byproduct of oxidative stress, 4-hydroxynonenal (4-HNE) induces apoptosis and lysosome dysregulation of RPE cells. In the present study, we evaluated cytokines production of RPE cells induced by 4-HNE by using cytokine array and confirmed that 4-HNE induced IL-6, IL-1 beta and TNF-alpha production in a concentration dependent manner. Specifically, 4-HNE also induced IL-10 and TGF-beta production in low concentration. Molecular analysis revealed that intracellular HSP70 inhibited 4-HNE-induced production of pro-inflammatory cytokines, and 4-HNE exerted proinflammatory effects in RPE cells by enhancing extracellular release of HSP70, as efflux inhibitor Methyl-beta-cyclodextrin (MBC) treatment significantly blocked the release of HSP70 and decreased IL-6 production of RPE cells induced by 4-HNE. Meanwhile, HSP70 inducer arimoclomol increased intracellular HSP70 production, but showed no influence on its extracellular level, also performed anti-inflammatory effects in 4-1-ME-stimulated RPE cells. Whereas the anti-inflammatory effects of paeoniflorin, an HSP70 inducer simultaneously promoted its extracellular efflux, was lower than arimoclomol. In addition, we further confirmed that MBC exhibited synergetic effect with both paeoniflorin and arimoclomol to inhibit the production of proinflammatory cytokines induced by 4-HNE. Taken together, these results indicate that HSP70 plays a vital role in regulating inflammation of RPE cells induced by oxidative stress and might be a potential novel target for clinical treatment of AMD.