Objective: Several studies have shown that some polymorphisms of genes encoding catechol-O-methyltransferase (COMT), the key enzyme in degrading dopamine, and norepinephrine and the human brain-derived neurotropic factor (BDNF), a nerve growth factor, are strong candidates for risk of schizophrenia (SCZ). In the present study, we aimed at examining the effects of COMT Val158Met (G>A) and BDNF Val66Met (G>A) polymorphisms on SCZ risk in a sample of Iranian population. Method: This case-control study included 92 SCZ patients and 92 healthy controls (HCs). Genotyping of both variants (COMT Val158Met (G>A) and BDNF Val66Met (G>A)) were conducted using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). Results: The findings revealed that the COMT Val158Met (G>A) polymorphism was not associated with the risk/protective of SCZ in all models (OR=0. 630, 95%CI=0. 299-1. 326, P=0. 224, GA vs. GG, OR=1. 416, 95%CI=0. 719-2. 793, P=0. 314, AA vs. GG, OR=1. 00, 95%CI=0. 56-1. 79, P=1. 00 GA+AA vs. GG, OR=1. 667, 95%CI=0. 885-3. 125, P=0. 11, AA vs. GG+GA, OR=1. 247, 95%CI=0. 825-1. 885, P=0. 343, A vs. G, ). However, BDNF Val66Met (G>A) variant increased the risk of SCZ (OR = 2. 008 95%CI = 1. 008-4. 00, P = 0. 047, GA vs. GG, OR = 3. 876 95%CI = 1. 001-14. 925, P = 0. 049. AA vs. GG, OR = 2. 272. 95%CI = 1. 204-4. 347, P = 0. 011, GA+AA vs. GG, OR = 2. 22 95%CI = 1. 29-3. 82. P = 0. 005, A vs. G). Conclusion: The results did not support an association between COMT Val158Met (G>A) variant and risk/protective of SCZ. Moreover, it was found that BDNF Val66Met (G>A) polymorphism may increase the risk of SCZ development. Further studies and different ethnicities are recommended to confirm the findings.