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Objective Hydrogen (H2) attenuates the development of atherosclerosis in mouse models. We aimed to examine the effects of H2 on atherosclerotic plaque stability. Methods Low-density lipoprotein receptor knockout (LDLR-/-) mice fed an atherogenic-diet were dosed daily with H2 and/or simvastatin. In vitro studies were carried out in oxidized-LDL (ox-LDL)-stimulated macrophage-derived foam cell model treated with or without H2. Key Results H2 or simvastatin significantly enhanced plaque stability by increasing levels of collagen and smooth muscle cells, as well as reducing macrophage and lipid levels in plaques. The decreased numbers of dendritic cells and increased numbers of regulatory T cells in plaques further supported the stabilizing effect of H2 or simvastatin. Moreover, H2 treatment decreased serum ox-LDL level and apoptosis in plaques with concomitant inhibition of endoplasmic reticulum stress (ERS) and reduction of ROS accumulation in the aorta. In vitro, like ERS inhibitor 4-phenylbutyric acid, H2 inhibited ox-LDL- or tunicamycin (an ERS inducer)- induced ERS response and cell apoptosis. In addition, like ROS scavenger N-acetyl-cysteine, H2 inhibited ox-LDL- or Cu2 + (an ROS inducer)-induced reduction in cell viability and increase in cellular ROS. Also, H2 increased Nrf2 (NF-E2-related factor-2, an important factor in antioxidant signaling) activation and Nrf2 siRNA abolished the protective effect of H2 on ox-LDL-induced cellular ROS production. Conclusions The inhibitory effects of H2 on the apoptosis of macrophage-derived foam cells, which take effect by suppressing the activation of ERS pathway and by activating Nrf2 antioxidant pathway, might lead to an improvement in atherosclerotic plaque stability.