OBJECTIVES: The cytosponge is a novel noninvasive screening method for Barrett’s esophagus (BE). Patients with GERD symptoms are at heightened risk for BE and may warrant screening, particularly if other risk factors are present. We analyzed the effectiveness and cost-effectiveness of cytosponge as a first-line screening method with endoscopic confirmation, compared to endoscopy alone, within a cohort of GERD patients.  METHODS: We used a validated microsimulation model of the natural history of esophageal adenocarcinoma (EAC) and precursor states, which was previously calibrated to SEER data on EAC incidence and mortality. The model incorporated cytosponge and endoscopic screening to assess their impact on clinical outcomes. We analyzed a cohort of 60 year old US males with GERD symptoms, comparing three screening strategies: no screening (S0), cytosponge screening with endoscopic confirmation of positive results (S1), and endoscopic screening (S2). In both S1 and S2, confirmed BE cases underwent surveillance and were treated with radio-frequency ablation therapy if they progressed to high grade dysplasia. Cytosponge was assumed to cost $500 per screen. RESULTS: Strategy S1 resulted in fewer total endoscopies compared to S2 (851/100K patients screened S1; 1868 S2) and was less costly ($2.1M/100K patients for S1, $2.3M for S2) but resulted in fewer average life-years (15091/100K patients in S1 versus 15092 in S2). S0 was the least costly ($1.0M), but resulted in the fewest average years of life (15076). The incremental cost-effectiveness ratios were $72,693/life-year for S1 compared to S0 and $156,681/life-year for S2 compared to S1.  In a sensitivity analysis, S1 was not on the efficiency frontier when cytosponge cost $621 or more. CONCLUSIONS: Initial cytosponge could be cost-effective as a screening method for patients with GERD, but only below a price threshold of $621.