Duodenal ulcers in children are associated with Helicobacter pylori gastric infection with cagA-positive strains, but factors linked to the host are poorly known. The authors evaluated the role of proinflammatory interleukin-1 gene cluster polymorphisms in the pathogenesis of duodenal ulcer. They studied prospectively 437 children 1 to years old, 209 of whom were H. pylori positive and 228 of whom were H. pylori negative. IL1B-511-C/T, -31T/C, and IL1RN Variable number of tandem repeats were genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism, PCR with confronting two-pair primers, and PCR, respectively. cagA status was evaluated by PCR. The role of the proinflammatory cytokine genotypes in the genesis of duodenal ulcer was evaluated before and after stratification of H. pylori status on logistic regression models. In the group of children without duodenal ulcer, no association was observed between H. pylori status and proinflammatory polymorphisms. Furthermore, no association between IL1 cluster genotypes and cagA status was seen in the H. pylori-positive children. However, increasing age, male sex, and IL1RN*2 were independently associated with duodenal ulcer. After stratification, in the H. pylori-positive children, increasing age, male sex, the presence of ILRN*2 allele, and cagA-positive status were independently associated with duodenal ulcer. The risk for the development of duodenal ulcer increased when a combined association of the presence of IL1RN*2 allele and infection by a cagA-positive H. pylori strain was the variable. This study provides evidence supporting independent roles of IL1RN*2 allele and cagA-positive status in the genesis of duodenal ulcer in children.