Oxidized low-density lipoprotein (ox-LDL) is a critical mediator of atherogenesis. Macrophage uptake of ox-LDL and their subsequent development into foam cells is the principal event in atherosclerosis. Interleukin-1β (IL-1β), a prototypic multifunctional cytokine involved in inflammation, has an important effect on the pathogenesis and progression of atherosclerosis. Here we show that the phagocytosis of ox-LDL can induce human macrophages to secrete IL-1β by activating the NLRP3 inflammasome, and we further show that the activation of the NLRP3 inflammasome is dependent on the generation of reactive oxygen species and is related to the cathepsin B pathway. Furthermore, ox-LDL can upregulate the expression of the pro-IL-1β protein, thus priming IL-1β secretion. Therefore, our results suggest that the role of ox-LDL in atherosclerosis-related inflammation may involve the activation of the NLRP3 inflammasome.