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Recent studies have shown that P-selectin promotes the early formation of atherosclerotic plaque. The aim of the present study was to evaluate whether the SELP gene single nucleotide polymorphisms (SNPs) are associated with presence of acute coronary syndrome (ACS) and with plasma P-selectin levels in a case-control association study. The sample size was estimated for a statistical power of 80%. We genotyped three SELP (SELP Ser290Asn, SELP Leu599Val, and SELP Thr715Pro) SNPs using 5’ exonuclease TaqMan assays in 625 patients with ACS and 700 healthy controls. The associations were evaluated with logistic regressions under the co-dominant, dominant, recessive, over-dominant and additive inheritance models. The genotype contribution to the plasma P-selectin levels was evaluated by a Student’s t-test. Under different models, the SELP Ser290Asn (OR = 0.59, pCCo-Dominant = 0.047; OR = 0.59, pCDominant = 0.014; OR = 0.58, pCOver-Dominant = 0.061, and OR = 0.62, pCAdditive = 0.015) and SELP Thr715Pro (OR = 0.61, pCDominant = 0.028; OR = 0.63, pCOver-Dominant = 0.044, and OR = 0.62, pCAdditive = 0.023) SNPs were associated with a lower risk of ACS. In addition, these SNPs were associated with low plasma P-selectin levels. In summary, this study established that the SELP Ser290Asn and SELP Thr715Pro SNPs are associated with a lower risk of developing ACS and with decreased P-selectin levels in plasma in a Mexican population.