We evaluated whether polymorphisms in genes coding molecules linked to the innate and adaptive immune response are associated with susceptibility to Helicobacter pylori infection. IL1B-511C-->T, IL1B-31T-->C, IL1RN allele 2, IL2-330T-->G, TNFA-307G-->A, TLR2Arg677Trp, TLR2Arg753Gln, TLR4Asp299Gly, and TLR5(392STOP) polymorphisms were determined in 541 blood donors. IL2-330T-->G allele carriers had a decreased H. pylori infection risk (OR=0.63, 95% CI=0.43-0.93) after adjustment for demographic and environmental factors. Hence, we investigated whether the polymorphism is functional by evaluating IL-2 serum concentration in 150 blood donors and 100 children. IL-2 pro-inflammatory and anti-inflammatory properties were indirectly investigated by determining serum IFN-gamma and IL-10/TGF-beta levels. The polymorphism was associated with increased mean IL-2 levels in H. pylori-positive adults (2.65 pg/mL vs. 7.78 pg/mL) and children (4.19 pg/mL vs. 8.03 pg/mL). Increased IL-2 was associated with pro-inflammatory activity in adults (IFN-gamma=18.61 pg/mL vs. 25.71 pg/mL), and with anti-inflammatory activity in children (IL-10=6.99 vs. 14.17 pg/mL, TGF-beta=45.88 vs. 93.44 pg/mL) (p<10(-3) for all). In conclusion, in the context of H. pylori infection, IL2-330 T-->G polymorphism is functional and is associated with decreased risk of infection in adults.