Gold nanoparticles (AuNPs) have been considered as an ideal candidate in various biomedical applications due to their ease of tailoring into different size, shape, and decorations with different functionalities. The current study was conducted to investigate the epigenetic alteration in the lung in response to AuNPs administration regarding microRNA-155 (miR-155) gene which can be involved in AuNP-induced lung pathogenesis. Thirty-two Wister rats were divided into two equal groups, control group and AuNPs treated group which received a single intravenous (IV) injection of plain spherical AuNPs (0.015 mg/kg body wt) with an average diameter size of 25±3 nm. Lung samples were collected from both the control and injected groups at one day, one week, one month and two months post-injection. The alteration of relative expression of gene and two of its putative target genes; tumor protein 53 inducible nuclear protein 1 and protein was investigated by real time PCR and protein S (PS) expression was analyzed by Western blotting technique. The obtained results revealed that AuNPs administration significantly increases the expression level of and reduce relative mRNA expression of and genes at one day post-injection. In contrast, a significant down-regulation of level of expression concurrent with up-regulation of expression level of and genes were shown at one week, one month and two months post-injection. PS levels were mirrored to their mRNA levels except for two month post-injection time point. These findings indicate epigenetic modulation in the lung in response to AuNPs administration regarding the gene which can be involved in AuNP-induced lung pathogenesis.