Background: Pesticide compounds are commonly used worldwide and in Egypt. Chronic low level exposure of humans to these compounds has resulted in many health adverse effects. There are many reports relating chronic kidney disease of unknown etiology (CKDu) epidemic to pesticide exposure including organophosphates (OP). Glutathione-S-transferase mu (GSTM1) and glutathione-S-transferase theta (GSTT1) are phase II xenobiotic metabolizing enzymes. Paraxonase 1 (PON1) is an enzyme linked to high-density lipoprotein. It can prevent oxidation of low-density lipoproteins and participates in organophosphate detoxification. Objective: To investigate the association of genetic polymorphism of GST (M1, T1) and PON1 Q192R with CKDu in pesticide exposed patients presented to Nephrology Unit, Internal Medicine Department, Zagazig University Hospitals, Sharkia Governorate. Methods: Gas chromatography- mass spectrometry (GC-MS) was used for detection of dialkyl phosphate metabolites in urine samples of subjects included in the study then genomic DNA isolated from the blood samples of 48 CKDu patient chronically exposed to pesticides giving positive result for dialkyl phosphate metabolites and matched control group was used to detect the presence or absence of the GSTM1 and GSTT1 genes (gene deletion) by multiplex polymerase chain reaction technique (multiplex PCR) and PON1 polymorphisms using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method. Conclusion: This study suggested that there is a correlation between chronic exposure to organophosphates and the risk of CKDu due to GSTM1 and GSTT1 genes deletions and PON1 gene polymorphisms.