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Atherosclerosis is a complex and progressive vascular disease characterized by lipid accumulation and inflammation. In recent years, the purinergic signaling system, particularly the P2X7 receptor, has been suggested to play a role in atherosclerosis pathogenesis through the regulation of inflammatory responses. The present study aimed to evaluate the association between P2RX7 rs1718119 (G > A) and rs2393799 (C > T) polymorphisms and the angiographic severity of coronary artery stenosis in a Turkish atherosclerosis population. Patients with angiographically confirmed atherosclerosis were enrolled and stratified according to the degree of coronary artery stenosis. Genotyping of the P2RX7 rs1718119 and rs2393799 polymorphisms was performed using real-time polymerase chain reaction-based fluorescence melting curve analysis (FMCA). No significant associations were observed between the genotype or allele distributions of either polymorphism and the angiographic severity of coronary artery stenosis. The investigated variants were not associated with angiographic stenosis severity. Associations with selected hematological and biochemical parameters should be regarded as exploratory and require further validation. These findings provide additional data on P2RX7 genetic variation in patients with atherosclerosis and highlight the need for further functional studies.