Besides environmental factors, the genetic background of an individual may contribute to the development and final outcome of peptic ulcer disease. Interleukin-1beta (IL-1beta) and the interleukin-1 receptor antagonist (IL-1ra) are cytokines that play a key role in modulating the inflammatory response in the gastrointestinal mucosa. This study aimed to investigate whether polymorphisms in the IL-1B and IL-RN genes are involved in the susceptibility to and final outcome of peptic ulcer disease. DNA from 179 unrelated Spanish Caucasian patients with peptic ulcer diseases and 99 ethnically matched healthy controls was typed for the TaqI polymorphism at position + 3954 in the IL-1B gene and the variable number of tandem repeats polymorphism in intron 2 of the IL-1RN gene. The determination of Helicobacter pylori status and non-steroidal anti-inflammatory drug (NSAIDs) use was studied in all patients and in controls. H. pylori infection and NSAID use were more frequent in ulcer patients than in controls. There were no significant differences in carriage rate, genotype and allele frequencies of the IL-1RN and the IL-1B(+3954) gene polymorphisms between peptic ulcer patients and controls. However, a strong allelic association between IL-1B and IL-1RN genes was found in duodenal ulcer patients (P < 0.0006). Logistic regression identified H. pylori infection and NSAIDs use as independent risk factors for peptic ulcer diseases whereas the simultaneous carriage of IL-1B(+3954) allele 2 and IL-1RN allele 2 was associated with reduced risk for duodenal ulcer disease (OR: 0.37, 95% CI = 0.14-0.9). Our data suggest that IL-1B and IL-1RN genes in addition to bacterial and environmental factors play a key role in determining the final outcome of peptic ulcer disease.