We aimed to evaluate the influence of Helicobacter pylori infection and IL-1/TNF gene polymorphisms on interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha gastric mucosal production. IL-1beta and TNF-alpha levels in homogenized biopsy specimens taken from the antrum and corpus of 81 patients were measured by enzyme-linked immunosorbent assay. Genomic DNA was typed for the IL1B-511, IL1B+3954, variable number of tandem repeat (VNTR) IL1RN, TNFA-308, TNFA-238, LTA NcoI, and LTA Bsi gene polymorphisms by polymerase chain reaction, restriction fragment length polymorphism, and TaqMan assays. H. pylori infection and CagA/VacA antibody status were determined by Western blot. IL-1beta and TNF-alpha protein levels were significantly higher in the gastric antrum of patients infected with H. pylori compared with uninfected patients [9.54 (5.07-16.28) vs. 4.55 (3.69-8.28) pg IL-1beta/mg protein, p = 0.004, and 1.5 (0.7-2.71) vs. 0.63 (0.3-1.26) pg TNF-alpha/mg protein, p = 0.001]. Among H. pylori-infected individuals, carriers of the IL1RN*2 allele had significantly higher antrum mucosal IL-1beta levels than noncarriers [15.97 (9.59-26.6) vs. 10.08 (7.72-13.33), p = 0.008]. No association between gastric mucosal TNF-alpha levels and genotypes of the TNFA and LTA gene polymorphisms was reported. Our results indicate that the VNTR polymorphism of the IL1RN gene influences IL-1beta gastric mucosal production in patients infected with H. pylori.