Background: Chronic low-level exposure to organophosphates is a significant hazard for the human. It was reported to have an adverse neurological complication, including Parkinson's disease (PD). Studying gene-environment interactions may elucidate the complex origins of idiopathic Parkinson's disease. Aim of the study: To investigate the relation between PON1 polymorphisms (PON1192Q/R) and its enzymatic activity and PD in patients with chronic exposure to organophosphorus pesticides. Patients and Methods: This study was conducted on 190 PD and 190 healthy persons. All participants were subjected to urine analysis for dialkyl phosphate metabolites (DAPs) detection, serum paraoxonase/arylesterase activity, and blood samples subjected to isolation of genomic DNA for PON1 polymorphisms genotyping using polymerase chain reaction–restriction fragment length polymorphism method. Results: There was no significant difference between patient and control groups regarding socio-demographic characteristics except for occupational history, as 85.3% of cases reported a history of pesticide exposure for more than ten years (56.8%). GC-MS analysis of urine samples revealed that 91.9% of cases have statistically significant detectable DAPs metabolites compared to 24.2% of controls. The mean value of serum PON1/arylesterase activity was statistically significantly lower in PD than in the control. The study revealed that RR homozygotes and R allele subjects showed a higher risk for PD (P<0.001 for each). Conclusion: The present study indicated that PON1 gene polymorphisms may contribute to susceptibility to Parkinson's disease in Egyptians. Parkinson's disease may importantly be influenced by PON1 polymorphism in interaction with organophosphorus exposure.