BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) affects approximately 0.5% of US children. Oral food challenges (OFCs) are frequently conducted to assess FPIES resolution in an observed setting, given the risk of severe reactions. However, it is unclear whether the observed OFC is universally cost-effective in all contexts vs gradually titrated home OFCs when caregivers are willing to accept a risk-to-benefit tradeoff. OBJECTIVE: To characterize the health and economic benefits of at-home vs supervised reintroduction OFC in patients with a history of mild-moderate index FPIES. METHODS: Cohort analyses evaluated the cost-effectiveness of a gradually titrated home vs clinical or hospital OFC using population simulations (n = 200,000 patients) and simulations in a rural New England population (n = 105). Severe FPIES reactions were defined as necessitating intravenous fluids. Fatality rates were defined as occurring approximately in 1/1,000,000 FPIES OFCs. Motor vehicle fatality rates were applied based on the travel distance to the OFC site. The cost-effectiveness threshold was set at 0,000,000 per fatality prevented. RESULTS: In the population simulation, the supervised OFC costs reached 11,088,445, with 18,680 severe reactions occurring (per-patient mean 0.093, SD 0.025), at a cost-per-fatality prevented of 24,233,328. In a simulation of a rural New England population with FPIES, the cost per severe reaction ranged from 1,790 to 6,304. CONCLUSION: A requirement for universally conducting FPIES challenges in an office-based or in-hospital setting is not cost-effective given extremely low FPIES reaction fatality rates, especially when compared with travel-based motor vehicle fatality rates. A shared decision-making approach may be appropriate to determine the challenge setting for patients with lower risk of severe reactions.