Background: Cyclin dependent kinase inhibitor (P21/WAFI) and murine double minute 2 (MDM2) participate in the cell growth regulation. In malignant tumors has been found altered expression of these gene products and has been associated with poor prognosis. Thus, the current study aimed to investigate P21-rs1801270 and MDM2-rs2279744 gene polymorphisms and their impact to lung cancer risk in Iraqi population. Methods: This study included a total of 140 lung cancer patients (101 males and 39 females) were diagnosed with non small cell lung carcinoma, compared with age and sex matched 150 healthy control individuals(105 males and 45 females), between the period of April 2017 to December 2020. The genotyping and allele frequency of C98A P21 and T309G MDM2 were examined by using PCR-RFLP technique. Results: Compared with the P21-98 C and MDM2-309T genotypes, we found that P21-98A and MDM2-309G variants were associated with an increased risk of NSCLC in Iraqi patients (OR= 5.0, C.I= 3.2-14.2, P<0.0001) for AA, (OR= 6.7, C.I= 4.0-12.4, P<0.0001)for GG and (OR= 2.7, C.I= 1.5-4.5, P<0.0003) for CA, (OR= 3.5, C.I= 1.8-5.4, P<0.0001) for GT genotypes. AA and GG genotypes were found to be associated with poor prognosis of NSCLC patients, significant associations were observed with stage (p= 0.02) and metastasis status (p 0.003) for P21 gene, (p= 0.01) and (p= 0.04) for MDM2 gene respectively of NSCLC in elderly and smoking patients. Furthermore, the presence of both P21 AA and MDM2 GG genotypes were associated with an increased the risk of lung cancer by five folds ( OR= 5.2, 95% C.I= 3.0-7.6, P< 0.05) for homogeneity genotypes compared to those who lacked from both genotypes. These results obviously indicate a multiplicative interaction between P21 AA and MDM2 GG genotypes in the risk of developing lung cancer. Conclusions: The incidence of both variant alleles P21 AA and MDM2 GG genotypes increased risk of lung cancer development in men, mainly in smokers older than 45 years. The expression of p21/WAF1 and MDM2 considered as two suitable indicators to predict the prognosis of NSCLC in Iraqi population.