Abstract: P53 tumor suppressor protein is a key component of genome guard. The p53 inactivation occurs frequently in many human cancers by mutation or over-expression of its specific inhibitor named MDM2 oncoprotein (Murine Double Minute-2), thus MDM2 inhibitors might offer the preventive and therapeutic strategies. In contrast, ATM (Ataxia Telangiectasia Mutated) tumor suppressor protein activates p53 protein. The MDM2 inhibitors such as Nutlin-3, HLI98 and MDM2 antisense oligonucleotides have been identified, but clinical validation is still pending. The Zataria multiflora Boiss. has antioxidant and antibacterial effects. To determine the correlation between the Zataria multiflora Boiss. and anti-carcinogenesis effects, we investigated the role of the essential oil of this plant on MDM2 and ATM genes expression using semi-quantitative RT-PCR in liver samples of 8 normal male rats. The results clearly showed that ATM and MDM2 gene expression increased and decreased, respectively, although the difference in ATM mRNA between target and control groups did not reach levels of significance. Our data implicated the essential oil of Zataria multiflora Boiss. as a down-regulator of MDM2 gene expression and may offer new tools for therapeutic intervention in the p53 pathway for cancer prevention and treatment.