To evaluate the effects of iron oxide nanoparticles on genes from different cell lines in this study, mouse macrophage RAW264.7 and hepatocyte Hepa1-6 cell lines were treated with DMSA-coated Fe3O4 nanoparticles. Two doses were used, 50 microg/mL and 100 microg/mL, respectively, for 24 hr and gene expression profile was detected by DNA microarrays. The gene expression patterns for the two cell lines greatly differed from each other when compared, revealing distinct cell-specific effects of the nanoparticles on the genes. It was found that the nanoparticles significantly influenced expression of genes in the RAW264.7 cells, showing complete difference from those of Hepa1-6 cells. More genes were downregulated in the RAW264.7 cells by two doses of the nanoparticles but up-regulated in the Hepa1-6 cells by two doses of the same nanoparticles. Moreover, the increase of nanoparticle dose greatly decreased up-regulation of genes but increased down-regulation of genes in the RAW264.7 cells. The influence of nanoparticles did not result in similar effect in the Hepa1-6 cells. Apart from the difference in gene expression patterns in the two cell lines, there were eight and seven genes which were consistently down-regulated and up-regulated by low-dose and high-dose of nanoparticles in the two cell lines, respectively, revealing the common effects of the nanoparticles on the genes in the two cell lines. These common effects on genes were caused by homeostatic processes, influenced by down-regulation of genes and immune responses, and also cell death, influenced by up-regulation of genes. The data from this study has shed new insights into the potential in vivo nanotoxicolgy of the DMSA-coated Fe3O4 nanoparticles.