Human monocytes can be classified into two subsets with distinctive characteristics. In this study, we report a difference in apoptotic potential between these two subsets with CD14+/low CD16+ monocytes being more susceptible than CD14+ CD16− monocytes to undergo spontaneous apoptosis and apoptosis induced by reactive oxygen species (ROS). By global transcriptomic and proteomic approaches, we observed that CD14+/low CD16+ monocytes expressed higher levels of pro-apoptotic genes and proteins such as TNFα, caspase 3, Bax and cytochrome c and showed more caspases 3 and 7 activities. They also exhibited greater aerobic respiration resulting in a higher production of ROS from the mitochondria. CD14+ CD16− monocytes, in contrast, showed higher expression of glutathione (GSH)-metabolizing genes such as GSH peroxidase and microsomal GSH S-transferase and were more resistant to oxidative stress than CD14+/low CD16+ monocytes. The apoptosis of CD14+/low CD16+ monocytes was ROS dependent as reducing ROS levels significantly reduced cell death. This is the first report of a differential apoptotic propensity of human monocyte subsets, and gaining a better understanding of this process may help to provide a better understanding of the roles of these subsets during homeostasis and under pathological conditions, particularly in situations in which high levels of oxidants are present.