Zinc oxide nanoparticles (ZnO NPs) are increasingly recognized for their cytotoxicity, whereas little is known about the toxicity mechanisms of ZnO NPs in human cells. To explore the possible molecular mechanisms for apoptosis induced by ZnO NPs, we investigated the relevant apoptotic signaling in human bronchial epithelial (16HBE) cells. ZnO NPs were found to induce intracellular reactive oxygen species (ROS) generation accompanied with the mitochondrial membrane potential (MMP, deltapsi(m)) reduction in 16HBE cells. Further, the expressions of two key apoptotic trigger regulators were determined by quantitative real time PCR and Western blot analysis. It demonstrated that following the exposure of 16HBE cells to ZnO NPs, both levels of mRNA and protein expression of c-Myc were significantly up-regulated, whereas the expressions of Bcl-2 mRNA and protein were down-regulated. Our results suggested that apoptosis induced by ZnO NPs might primarily involve the regulations of c-Myc and Bcl-2 gene expressions besides decline of MMP in 16HBE cells.