Helicobacter pylori is one of the major risk factors involved in the development ofgastritis and gastric cancer (GC). H. pylori infection leads to increased production of pro-inflammatory cytokines by the host. Carriage of specific polymorphisms in cytokine genes may be associated with host susceptibility to the development of GC. We investigated the role of host genetic factors including polymorphisms of IL-1B and IL-1RN in correlation with gastritis and GC in H. pylori infected Pakistani population. A total of 230 gastritis cases and 100 GC cases were genotyped for IL 1B-511 and IL-1RN penta-allelic variable number of tandem repeats (VNTRs). A combination of IL-1B-511*T and IL-1RN*2 alleles (OR 19.064; 95% CI 2.319-156.7; p = 0.001) in H. pylori infected individuals had markedly increased risk of GC development. In Pakistani population, an increased risk of GC development is associated with the carriage of IL-1B-511*T and IL-1RN*2 alleles. Synergistic effect of H. pylori infection and IL-1B-511*T/IL-1RN*2 genotypes was also observed in association with significantly higher risk of developing GC. Further prospective and large scale studies are needed to establish the clinical impact of these findings.