Background/Aim: Primary brain tumors are unique tumors due to their different pathobiological behavior, while they rarely metastasize outside the central nervous system. Regarding the oncogenesis of primary brain tumors, it was shown that changes in functions of p16 and mouse double minute 2 homolog (MDM2) are related to tumor pathogenesis by enhancing cell proliferation and malign development. The present study aims to evaluate the possible associations between cyclin-dependent kinase 2 (CDKN2) p16 540 C>G and 580 C>T, MDM2 single nucleotide polymorphism 309 (SNP309) T>G polymorphisms and primary brain tumor. Materials and Methods: Using polymerase chain reaction-restriction fragment length polymorphism technique, we determined SNPs in 67 patients with primary brain tumors and 71 healthy volunteers without malignancy. Results: The frequency of CC genotype for CDKN2 p16 540 C>G was significantly two-fold higher (p<0.001) and possessing a C allele conferred a similar to 7-fold increased risk (p=0.005) of primary brain tumor. We also found that the CC genotype produced a higher similar to 4-fold risk of glioma (p= 0.001) and the G allele had a possibly protective role against meningioma (similar to 4.8- fold reduced risk, p= 0.001). We found no significant associations for CDKN2 p16 580 C>T and MDM2 SNP309 T>G variants between cases and controls. CGT haplotype was significantly less frequent in patients with primary brain tumors and glioma cases (p= 0.009 and p= 0.028, respectively) than controls. CGG haplotype was significantly less frequent in patients with meningioma versus the control group (p= 0.023). Conclusion: These findings show that CDKN2 p16 540 C>G, CDKN2 p16 580 C>T and MDM2 SNP309 T>G variants and their haplotypes may be risk factors for the development of primary brain tumors, especially of glioma.