Significance Helicobacter pylori is a bacterium that infects the stomach of approximately 50%of the worlds population and is associated with the development of peptic ulcer disease and gastric malignancy. Objective Previous work has suggested that immunization of mice can prevent experimental infection with H. pylori. However, since mice are not naturally infected with H. pylori, the relevance of this finding for humans is not clear. Since rhesus monkeys are often naturally infected with H. pylori, they may provide a more relevant animal model. The present study was designed to determine if infection with H. pylori following experimental innoculation could be prevented by immunization with urease, one of the major immunogenic proteins produced by the bacterium. Results Eleven rhesus monkeys were hand reared from birth and documented by endoscopy, serology, and urea breath test to be free of infection with H. pylori. The animals were randomly divided into a control group (N=2), a group receiving oral urease with E. coli LT adjuvant (N=4), and a group receiving intramuscular urease with a novel adjuvant (N=5). Immunizations were delivered a total of 4 times, followed 1 week later by challenge with H. pylori derived from rhesus monkeys. Three weeks after immunization the animals were endoscoped and biopsies were obtained for quantitative culture and histology. All animals also underwent repeat urea breath testing. The results indicated that all animals were infected to varying degrees. There was no relationship between quantitative culture and immunization, or between gastric mucosal inflammation and immunization. These results indicate that previous data in mice which suggested that urease might serve as an effective vaccine may not be relevant to primates. Future Directions The rhesus monkey model will be further developed for studies of additional vaccine candidates against H. pylori. KEYWORDS Helicobacter pylori, immunization, urease