Introduction. The modulation of the purinergic receptor P2X7 may be implicated in human carcinogenesis. The 1513A>C and 489C>T polymorphisms of P2X7R gene induces loss-of-function and gain-of-function, respectively. Aim. To assess the frequency of both 1513A>C and 489C>T polymorphisms in patients with papillary thyroid carcinoma (PTC), and to evaluate the possible association with clinical and histological features. Patients and methods. P2X7R analysis was performed in lymphocytes from 121 PTC patients (100 women; aged 43.4+/-13.6 years), 100 matched healthy subjects and, 80 patients with nodular goitre. Results. The minor allele frequency for 1513A>C polymorphism in PTC patients with the classical variant was similar to controls (0.21 and 0.20, respectively), while resulted significantly increased in patients with the follicular variant (0.36, p=0.01 vs classical variant and 0.005 vs controls). In detail, 13.6% of patients with PTC follicular variant were homozygous for the 1513C allele as compared to 2.6% of patients with the classical variant and 2% of controls. Moreover, a positive relationship between 1513A>C polymorphism and either cancer diameter (Rho=0.22; p=0.02) or TNM stage (Rho=0.38; p<0.001) was found. No significant difference in the genotype frequency of 489C>T polymorphism between PTC patients and healthy controls was observed (0.42 and 0.47, respectively). Conclusions. Our data show, for the first time, a strong association between 1513A>C polymorphism of P2X7R gene and the follicular variant of PTC. Further studies are needed to confirm the possible role of this polymorphism as novel clinical marker of PTC follicular variant and its usefulness in selecting patients with different clinical outcome.