To study the toxicity mechanism of ZnO nanoparticles on mouse macrophages, the toxic effect of different ZnO nanoparticles on mouse alveolar macrophages (MH-S) was investigated in this study. The results showed that the 24h IC(50) of four ZnO particles were 48.53, 47.37, 45.43 and 26.74μg/ml for bulk ZnO, 100nm, 30nm and 10-30nm ZnO particles, respectively. At the concentration of 10μg/ml and below, dissolved zinc ions induced metallothionein synthesis, enhanced cellular resistance to oxidative stress. ZnO particles mainly induced cell apoptosis. When the concentration of ZnO particles was 20μg/ml and above, excessive zinc destroyed mitochondrial function and cell membrane, caused cell necrosis. Dissolved zinc ions first cause toxicity in MH-S cells. However, the toxic effect of dissolved zinc ions may exist a threshold on mouse macrophages, inducing about 50% cell death. The toxic difference of different ZnO particles mainly depended on the effect of nondissolved ZnO particles.