Twin studies evidence that genetic factors of the host influence the acquisition and the clinical outcome of Helicobacter pylori infections in addition to bacterial and environmental factors. In the tumor necrosis factor (TNF) alpha-gene, allelic frequencies of the polymorphic microsatellite TNFa and the promoter polymorphism TNF-308 were studied for 209 H. pylori+ patients and compared to 184 H. pylori- controls. In the H. pylori+ group 34 individuals suffered from duodenal ulcer and 45 from gastric ulcer. Genotyping of the TNFa microsatellite and TNF-308 polymorphisms was performed after polymerase chain reaction by polyacrylamide gel electrophoresis (PAGE) and allele-specific oligonucleotide hybridizations, respectively. The phenotype frequency of microsatellite allele TNFa6 was lower in the H. pylori+ females as well as infected females with gastric ulcer compared to uninfected controls. Infected men with duodenal ulcer had a decreased frequency of allele TNFa10. The genotype TNF1/TNF1 of the polymorphism TNF-308 is a risk factor for duodenal ulcer in H. pylori+ females; p = 0.01; relative risk (RR) = 10.7; corrected p-value (Pc) = 0.05. Thus, the TNF region is crucial in the complex genetic predisposition for H. pylori infection for certain patient subgroups.