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Patients with left main (LM) coronary artery disease (CAD) are at the highest risk of cardiovascular events. We evaluated possible gene polymorphisms of tumor protein 53 (TP53, rs1042522, p.Arg72Pro) that can differentiate LM-CAD from patients with more peripheral CAD (MP-CAD) and healthy participants (control group) in 520 individuals (LM-CAD, n = 175; MP-CAD, n = 185; and control group, n = 160). Patients with LM-CAD had the lowest Arg/Arg genotype frequency (36.0%) compared with the MP-CAD (57.3%) and control groups (61.9%), P < .001 for both comparisons. Similarly, the Arg allele was more frequent in the control group than in patients with MP-CAD (78.8% vs 73.2%; P = .007) and LM-CAD (78.8% vs 64.0%; P < .001). The Arg/Pro genotype was more frequent in the LM-CAD group compared with the MP-CAD and control groups (56.0, 31.9, and 33.8, respectively, P < .001 for both comparisons). Furthermore, the frequency of Arg/Arg genotypes was the lowest in the LM-CAD group compared with the MP-CAD and control groups. Knowing that TP53 is an antioncogene protein that acts as a tumor suppressor and regulator of apoptosis, the lowest frequency of Arg/Arg genotype observed in these high-risk patients may indicate lower protection from the atherosclerosis process. Replication studies are needed to evaluate this association.