End-stage renal disease (ESRD) is a state of chronic inflammation. DNA methylation is a major epigenetic modification that has the potential to silence gene expression. IFN-γ and suppressor of cytokine signaling (SOCS) are essential modulators of inflammation. The current study aimed to determine the methylation status of IFN-γ, SOCS1 and SOCS3 promoter regions in DNA isolated from peripheral blood of ESRD patients and controls, in order to correlate this methylation status with the clinical features of ESRD. Ninety six ESRD patients and 96 healthy ethnically, age and gender matched controls were included in the study. The promoter methylation of the studied genes was assessed using the methylation-specific polymerase chain reaction (MSP). Most of our samples were positive for IFN-γ promoter methylation. Full unmethylation was observed only in the ESRD group (7.3%), and statistical difference was observed among groups (P=0.02). IFN-γ unmethylation was associated to a decrease in estimated glomerular filtration rate (eGFR) and an increase in both serum creatinine and total cholesterol levels. For SOCS1 promoter methylation, partial and full methylation were observed only in ESRD patients (5.2% and 2.1%, respectively); however no methylation was detected in controls (P=0.014). SOCS3 promoter methylation was not detected in either the patient or control group. In conclusion, the methylation profile of IFN-γ and SOCS1 promoter regions play an important role in the pathogenesis of ESRD. The present study highlights the role of epigenetics in disease progression.