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This study aimed to assess the impact of glutathione S-transferase M1 (GSTM1) and N-acetyltransferase 2 (NAT2) polymorphisms on renal cell carcinoma (RCC) risk in Mongolian individuals, both independently and in combination with smoking and urinary tract diseases (UTDs). Methods: This hospital-based case-control study included 88 histologically confirmed RCC patients and 88 cancer-free controls, matched by age and sex. Genotyping of GSTM1 and NAT2 polymorphisms was performed using PCR-RFLP. Results: There were 34 men, and 54 women, with a mean age of 51.9 ± 13.2 years. The results revealed that NAT2 low acetylator genotype significantly increased risk of RCC (cOR=2.077, 95%CI=1.072-4.025, p=0.03). Notably, WT/M3 genotype was significantly associated with RCC risk (aOR=9.1, 95% CI=1.138–72.783; p=0.037). GSTM1-positive genotype significantly increased RCC risk when combined with NAT2 low acetylator genotypes (cOR=3.304, 95% CI=1.311–8.327, p=0.011). Among smokers, individuals with GSTM1-null genotype increased risk of RCC (cOR=4.654, 95% CI=1.458-14.86, p=0.009). Additionally, NAT2 low acetylator genotype significantly increased RCC risk in smokers (cOR=6.596, 95% CI=2.26–19.255, p=0.001). Furthermore, both GSTM1 and NAT2 genotypes were associated with significantly increased RCC risk following stratification by a history of urinary tract diseases. Conclusion: The findings suggest that the NAT2 WT/M3 polymorphism, along with smoking and UTDs, contributes to RCC susceptibility in Mongolian cases.