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Background: Anti-oxidants were investigated in several studies as a preventive strategy for prevention of contrast-induced nephropathy (CIN). Omega-3 polyunsaturated fatty acids have antioxidant properties; however, their role in the prevention of CIN is still unknown. Therefore, in this study, we aimed to evaluate the efficacy of omega-3 supplementation in the prevention of contrast-induced nephropathy following elective percutaneous coronary intervention in patients with chronic kidney disease. Methods: This is a double-blinded and randomized clinical trial. Eighty eligible patients with glomerular filtration rate of 30-60 mL/min/1.73 m2, scheduled to undergo elective PCI, were randomly divided into omega-3 (a single dose of 2500 mg omega-3 12 hours before PCI plus hydration therapy) or control (placebo plus hydration therapy) groups. Blood specimens for measuring serum creatinine and cystatin C were collected from each patient at baseline and 24 h after PCI. Results: Omega-3 did not show any significant effect on post-PCI serum creatinine and cystatin C compared to the controls. In addition, serum creatinine analysis showed that CIN occurred in 6 (16.2%) patients of the omega-3 and 4 (9.3%) patients of the control group (P = 0.50). Conclusions: Our results could not support the protective effect of a single dose of omega-3 in decreasing serum creatinine, serum cystatin C, and the incidence of CIN in patients with CKD undergoing PCI. To better evaluate the effect of omega-3, future studies with higher and/or multiple doses of omega-3 are highly recommended.