The present case-control study was carried out to investigate the association of polymorphism in cytochrome P450 2D6 (CYP2D6) and N-acteyltransferase-2 (NAT2), that are involved in the metabolism and detoxification of chemicals causing Parkinson disease (PD) like symptoms, with PD. Our data demonstrated increased frequency of CYP2D6*2 (1749G/C and 2938C/T), CYP2D6*4 (1934G/A) and CYP2D6*10A (188C/T) polymorphisms in PD cases when compared to the controls. Statistical analysis revealed the significant association of CYP2D6*4 (1934G/A) and CYP2D6*10A (188C/T) polymorphism with PD. Likewise, increased frequency of NAT2*7 polymorphism that leads to the slow acetylator phenotype was observed in PD patients with more than fivefold increased risk (OR: 5.55; 95%CI: 0.56–54). No change was observed in the frequency of NAT*5 or NAT*6 alleles in the cases. Further, cases carrying combination of heterozygous genotypes of CYP2D6*4 or CYP2D6*10A(188C > T) and NAT2*5 were found to be at significantly higher risk for PD demonstrating the importance of gene-gene interactions in determining susceptibility to PD.