Background: Keratoconus (KC) is a degenerative eye disease which results from thinning of the cornea and causes vision distortion. Oxidative stress damage to KC corneas may be because of the failure of corneas to process reactive oxygen species which leads to corneal thinning and loss of vision. Genetic variants in antioxi-dant defense genes such as catalase (CAT) and glutathione peroxidase (GPX) can decrease antioxidant capacity or increase oxidative stress and alter the risk of KC in patients. We investigated and evaluated the effects of single nucleotide Polymorphisms in CAT, GPX-1 on the risk of KC in an Iranian population sample. Methods: This case-control study was performed on 140 patients with KC and 150 healthy control subjects in a sample of Iranian population from Zahedan, southern Iran in 2015. Genotyping of CAT rs7943316 and GPX-1 rs1050450 Polymorphisms was done using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Results: CAT rs7943316 A/T, AA genotype and A allele have a protective role against disease (OR =0. 28, 95% CI =0. 13-0. 61, P=0. 001 and OR = 0. 50, 95% CI =0. 35-0. 72, P=0. 0001, respectively) and decreased the risk of KC. Moreover, GPX-1 rs1050450 T allele increased the risk of KC in comparison with C allele (OR = 1. 42, 95% CI = 1. 01-2. 03, P=0. 03). Conclusion: CAT rs7943316 A/T, AA genotype, and A allele decreased the risk of KC. Moreover, in GPX-1 rs1050450 C/T polymorphism, T allele was associated with an increased risk of KC in our population.