OBJECTIVES: The population prevalence of eosinophilic esophagitis (EoE) is ~7% in adults. Current American Gastroenterology Association guidelines recommend endoscopic biopsy (Bx) in patients with symptoms of dysphagia. We conducted a cost-effectiveness model to determine if endoscopic Bx is cost effective in patients with refractory gastroesophageal reflux disease (GERD) without dysphagia. METHODS: We designed a 5-year Markov model to compare costs and quality-adjusted life years for a cohort of 35-year-old patients with GERD refractory to proton pump inhibitor (PPI) therapy. We compared upper endoscopy (EGD) with and without Bx for EoE. We modeled that patients with EoE who did not undergo initial biopsy would wait 5 years until the diagnosis would be established via a second endoscopy with biopsy. RESULTS: In patients with refractory GERD without dysphagia, endoscopic Bx for EoE was associated with an incremental cost-effectiveness ratio (ICER) of $51,420 per quality of life year (QALY). The upper endoscopy with biopsy arm cost $12,490 per patient and was associated with 4.080 QALYs, compared with EGD without Bx arm that cost $12,280 and was associated with 4.076 QALYs. The ICER was <$50,000 per QALY when the prevalence of EoE exceeded 8%, or the time of missed diagnosis was 6 years or greater. The biopsy arm was also cost effective if the QALY associated with symptomatic GERD was ≤0.93, cost of 3-month course of PPI therapy ≥$770 cost of fluticasone <$650, probability of EoE resolved on PPI ≤25%, symptom resolution on fluticasone ≥70%, cost endoscopy with biopsy ≤$520, or the cost of endoscopy without biopsy exceeded $300. CONCLUSIONS: Upper endoscopy with Bx for EoE appears to be a cost-effective approach in patients when the prevalence of EoE is 8% or greater.