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ABSTRACTTonsillar disease (recurrent tonsillitis and/or tonsillar hypertrophy) is one of the most common human disorders, with Streptococcus pyogenes(group A beta-hemolytic streptococcus [GAS]) and Haemophilus influenzaerepresenting the most common pathogens. Until now, no study has investigated why some individuals are more susceptible to tonsillar infections caused by specific bacteria than others. The aim of this study was to uncover possible associations between common Toll-like receptor gene (TLR) polymorphisms and tonsillar disease. The TLR2-R753Q, TLR4-D299G, and TLR4-T399I polymorphisms were determined in a cohort of 327 patients subjected to tonsillectomy due to recurrent tonsillitis (n= 245) and tonsillar hypertrophy (n= 82) and 245 healthy bone marrow donors. Associations of the aforementioned polymorphisms with the isolated bacterial strains after tonsillectomy were also investigated. Interestingly, carriers of the TLR4polymorphisms displayed an approximately 3-fold increased risk for GAS infections (for TLR4-D299G, odds ratio [OR] = 2.81, 95% confidence interval [CI] = 1.16 to 6.79, P= 0.038; for TLR4-T399I, OR = 3.01, 95% CI = 1.29 to 7.02, P= 0.023), and this association was more profound in patients with recurrent tonsillitis. On the contrary, the presence of the TLR4-T399I polymorphism was associated with a 2-fold decreased risk of Haemophilus influenzaecarriage (OR = 0.38, 95% CI = 0.15 to 0.96, P= 0.038). In the end, no significant differences were observed, considering the genotype and allele frequencies of the above-mentioned polymorphisms, between patients and controls. Our findings indicate that, regarding tonsillar infections, TLR4polymorphisms predispose individuals to GAS infection, while they are protective against Haemophilus influenzaeinfection. This result further elucidates the role that host immune genetic variations might play in the susceptibility to common infections and tonsillar disease.