Objective To estimate the cost-effectiveness of noncardia gastric adenocarcinoma (NCGA) screening strategies based on new biomarker and endoscopic technologies. Design Using an intestinal-type NCGA microsimulation model, we evaluated the following one-time screening strategies for US men:(1) serum pepsinogen to detect gastric atrophy (with endoscopic follow-up of positive screen results),(2) endoscopic screening to detect dysplasia and asymptomatic cancer (with endoscopic mucosal resection (EMR) treatment for detected lesions) and (3) Helicobacter pylori screening and treatment. Screening performance, treatment effectiveness, cancer and cost data were based on published literature and databases. Subgroups included current, former and never smokers. Outcomes included lifetime cancer risk and incremental cost-effectiveness ratios (ICERs), expressed as cost per quality-adjusted-life-year (QALY) gained. Results Screening the general population at age 50 years reduced the lifetime intestinal-type NCGA risk (0.24%) by 26.4% with serum pepsinogen screening, 21.2% with endoscopy and EMR and 0.2% with H. pylori screening/treatment. Targeting current smokers reduced the lifetime risk (0.35%) by 30.8%, 25.5%, and 0.1%, respectively. For all subgroups, serum pepsinogen screening was more effective and more cost-effective than all other strategies, although its ICER varied from 76000/QALY(currentsmokers)to 105 400/QALY (general population). Results were sensitive to H. pylori prevalence, screen age and serum pepsinogen test sensitivity. Probabilistic sensitivity analysis found that at a 100000/QALYwillingness-to-paythreshold,theprobabilitythatserumpepsinogenscreeningwaspreferredwas0.97forcurrentsmokers.ConclusionsAlthoughnotwarrantedforthegeneralpopulation,targetinghigh-risksmokersforserumpepsinogenscreeningmaybeacost-effectivestrategytoreduceintestinal-typeNCGAmortality.