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The present study was aimed at providing a better understanding of the influence of silver nanoparticles (AgNPs) on the p53 tumor suppressor protein. Cell line A549 was exposed to a range of concentrations of AgNPs, and a time course (up to 72 h) of cell viability was determined. We also determined the time course of gene and protein expression of p53, p21, murine double minute 2 (MDM2) and caspase-3. The expression of all of these proteins was also determined after daily exposure of the cells to 10 µg/mL of AgNPs for 7 days, or after discontinuous exposure by treating the cells every 3 days, for 15 or 30 days. Moreover, epigenetic changes in the acetylation of the histone H3 protein and in global DNA methylation patterns were determined after 72 h of exposure. Results showed that daily exposure to low doses of AgNPs, or a single exposure to high concentrations for 72 h, decreased gene and protein expression of p53, p21, MDM2 and caspase-3 in A549 cells. In contrast, a discontinuous exposure to low doses or a single exposure to low concentrations for 72 h increased the levels of the active forms of p53 and caspase-3, as well as the p21 and MDM2 protein levels. In addition, exposure to high concentrations of AgNPs for 72 h induced higher levels of global DNA methylation and global histone H3 deacetylation in A549 cells. These results provide new information on the toxic action of AgNPs.