The goal of this Program Project has been and continues to be the multi-disciplinary study of the etiology of gastric cancer. This neoplastic disease is second only to lung cancer in incidence and mortality worldwide. In the United States gastric cancer rates have decreased considerably. There are, however, high-risk groups, especially African Americans, Amerindians, and immigrants from Asia, Northern/Eastern Europe and Latin America. It has become increasingly clear that a major etiologic factor is chronic infection with Helicobacter pylori. About one half of today.s world population is infected, especially groups of lower socioeconomic status. The International Agency for research on Cancer has classified Helicobacter infection as a class 1 carcinogen. There are great differences in the outcome of the infection. Most infections are mild and subclinical. Clinical infections may lead to duodenal ulcer accompanied by non-atrophic gastritis, which does not increase gastric cancer risk, or to multifocal atrophic gastritis, which may lead to gastric ulcer and gastric cancer. Our general hypothesis is that the immune and inflammatory responses determine the outcome of the infection. Our Program Project explores the dynamics of the response with immunologic and histopathologic techniques in adults and children (Project 1,2 and 3). Two epidemiologic projects are also proposed: 1) follow-up of the chemoprevention cohort, which explores the natural history of infection after eradication attempts (Project 1); and 2) study of the dynamics of infection and reinfection in children of a hyper-endemic area in search for answers to the critical events in initiating the possible carcinogenesis pathway, namely persistence of infection in childhood. (Project 3).