Background It is unknown whether eradication of Helicobacter pyiori infection prevents development of gastric adenocarcinoma. To determine whether screening and treatment trials are warranted, we conducted a cost-effectiveness analysis to estimate the costs and benefits associated with screening for H pylori at age 50 and treating those individuals infected with antibiotics. Methods We compared two interventions: (1) screen for H pylori and treat those with a positive rest, and (2) do not screen and do not treat. Estimates of risks and costs were obtained by review of published reports. Since the efficacy of H pyiori therapy in cancer prevention is unknown, we did sensitivity analyses, varying this estimate widely. In our base-case analysis, we assumed that H pylori treatment prevented 30% of attributable gastric cancers. Findings In the base-case analysis, 11 646 000 persons in the US would be screened and 4 658 400 treated, at a cost of $996 million. Cost-effectiveness was $25 000 per year of life saved, Cost-effectiveness was sensitive to the efficacy of the cancer prevention strategy. At low efficacy rates (<10%), the screening programme was more expensive (>$75 000 per year of life saved), In a high-risk group such as Japanese-Americans, however, screening and treatment required less than $50 000 per year of life saved, even at 5% treatment efficacy. Interpretation Screening and treatment for H pyiori infection is potentially cost-effective in the prevention of gastric cancer, particularly in high-risk populations. Cancer prevention trials are strongly recommended.