INTRODUCTION Inflammation has gained a pivotal role in the pathophysiology of Acute Coronary Syndrome (ACS). TNF-α is a pro-inflammatory cytokine that could be a potential biomarker in ACS due to its multiple functions. The rs1799964 TNFA polymorphism (-1031T>C) has been associated with a decrease in gene transcription and cytokine levels. OBJECTIVE To determine the association of rs1799964 TNFA polymorphism and TNF-α soluble levels in ACS. METHODS A total of 251 patients diagnosed with ACS and 164 individuals without cardiovascular diseases classified as the reference group (RG), were included. The rs1799964 polymorphism was genotyped by PCR-RFLP. Soluble protein levels were determined by ELISA. Statistical analyses were performed using chi square and U-Mann Whitney tests. RESULTS The genotype and allele frequencies were different between ACS and RG (OR=0.317, p=0.01; OR=0.688, p=0.03 respectively). ACS patients had higher soluble TNF-α levels compared with the RG (31.08 vs 23.00pg/mL, p<0.001); according genotype significant differences were observed (T/T: 24.06 vs T/C: 34.95pg/mL, p=0.0001) in patients. In the RG, T/T carriers showed discrete lower levels than C/C genotype (22.14 vs 27.83pg/mL, p=0.04). CONCLUSIONS The -1031C allele of the TNFA polymorphism confers protection for the development of ACS. The T/C genotype carriers had higher TNF-α serum levels compared to the T/T genotype in ACS. In addition, the -1031T>C TNFA polymorphism was associated with dyslipidemia in ACS in a Western Mexican population.