Abstract Bats harbor various viruses without severe symptoms and act as their natural reservoirs. The tolerance of bats against viral infections is assumed to originate from the uniqueness of their immune system. However, how immune responses vary between primates and bats remains unclear. Here, we characterized differences in the immune responses by peripheral blood mononuclear cells to various pathogenic stimuli between primates (humans, chimpanzees, and macaques) and bats (Egyptian fruit bats) using single-cell RNA sequencing. We show that the induction patterns of key cytosolic DNA/RNA sensors and antiviral genes differed between primates and bats. A novel subset of monocytes induced by pathogenic stimuli specifically in bats was identified. Furthermore, bats robustly respond to DNA virus infection even though major DNA sensors are dampened in bats. Overall, our data suggest that immune responses are substantially different between primates and bats, presumably underlying the difference in viral pathogenicity among the mammalian species tested.