AbstractBrain microglial cells are thought to undergo apoptosis following the exposure to inflammatory stimuli such as lipopolysaccharide (LPS) and IFNγ, which is considered as an autoregulatory mechanism to control their own activation state. Here, we report that N‐myc constitutes a novel apoptotic pathway of LPS/IFNγ‐activated microglia. The expression of N‐myc was synergistically enhanced by LPS and IFNγ in microglia. Tetracycline‐based conditional expression of N‐myc sensitized microglia to nitric oxide (NO)‐induced apoptosis. Knockdown of N‐myc expression using small interfering RNA (siRNA) attenuated LPS/IFNγ‐induced microglial apoptosis. An increase in N‐myc expression, however, did not affect microglial production of NO or TNFα. The synergistic effect of LPS/IFNγ on the microglial N‐myc induction was mediated through Janus kinase (JAK)/STAT1 (signal transducer and activator of transcription 1) pathway. Taken together, LPS/IFNγ‐induced N‐myc participated in the activation‐induced cell death of microglia by sensitizing the cells to NO‐induced apoptosis; however, N‐myc did not influence the processes of inflammatory activation of microglia.