Objective— The pathogenic role of macrophage apoptosis in atherosclerosis is still debatable, but it is considered to be a suppressor of plaque progression in early stages but a promoter of plaque necrosis in advanced stages. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a pivotal role in stress-induced apoptosis. In the current study, we investigated the functions of ASK1 in hyperlipidemia-induced atherosclerosis. Methods and Results— We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1 −/− /apoE −/− ) and analyzed atherosclerosis in ASK1 −/− /apoE −/− mice fed a high-cholesterol diet for 12 weeks. ASK1 −/− /apoE −/− mice had accelerated hyperlipidemia-induced atherosclerosis, which was characterized by less apoptosis of macrophages and fewer necrotic areas, and more macrophages and elastolysis compared with apoE −/− mice. Bone marrow transplantation from ASK1 −/− or wild-type to apoE −/− mice confirmed the above observation that the recipient mice of ASK1 −/− donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors. Conclusion— These findings suggest that ASK1 suppresses hyperlipidemia-induced atherosclerosis via increased macrophage apoptosis and that ASK1 may cause pronounced plaque vulnerability via necrotic core development.