Metabolic syndrome (MetS) results from the interaction between environmental and genetic factors. Several previous studies considered the role of selenium in developing MetS. Two selenoproteins, selenoprotein S (SelS), and the Selenoprotein P (SePP) play an important role in antioxidative defense and therefore susceptibility to MetS. The involvement of SNPs in SEPP1 and SEPS1 have not been studied in MetS subjects. This study aims to investigate the association between the risk of MetS and four polymorphisms SEPS1 (rs28665122, rs4965373), SEPP1 (rs7579, rs3877899) in an Iranian population. The sample of this case-control study consisted of 132 Iranian patients with cardiovascular disease (71 MetS and 65 non-MetS subjects) from December 2015 to March 2016. Demographic data, medical history, and para-clinical were measured, and Taqman probes were used for allelic discrimination. The level of the SelS and the SePP were measured by the ELIZA method. No significant differences were found in the genotype frequencies of SEPS1 (rs4965373, rs28665122), SEPP1 (rs7579, rs3877899) in patients with MetS and the non-MetS group. The mean of SelS in MetS subjects with SEPS1 (rs4965373) GG genotype is significantly lower than the non-MetS group (4496.99 ± 3688.5 vs. 6148.6 ± 1127.0, P = 0.009). The mean of SePP in MetS subjects with SEPP1 (rs3877899) GG genotype is significantly lower than the non-MetS group (40.73 ± 8.44 vs.83.91 ± 21.33, P = 0.002). The mean of SePP in MetS subjects with SEPP1 (rs7579) GG genotype is lower than the non-MetS group (55.52 ± 16.7 vs. 109.48 ± 29.78, P = 0.01). In summary, the results of this study does not indicate significant differences in the SEPP1 (rs7579, rs3877899) and SEPS1 (rs4965373, rs28665122) genotypes between MetS and non-MetS subjects. However, the results show that the mean of expression of SelS and SePP decreased in the subjects with SEPP1 (rs7579) GG and SEPP1 (rs3877899) GG.