Background: A 6-food elimination diet in pediatric eosinophilic esophagitis (EoE) is difficult to implement and may negatively affect quality of life (QoL). Less restrictive elimination diets may balance QoL and efficacy., Objective: We performed a multisite, randomized comparative efficacy trial of a 1-food (milk) elimination diet (1FED) versus 4-food (milk, egg, wheat, soy) elimination diet (4FED) in pediatric EoE., Methods: Patients aged 6 to 17 years with histologically active and symptomatic EoE were randomized 1:1 to 1FED or 4FED for 12 weeks. Primary end point was symptom improvement by Pediatric Eosinophilic Esophagitis Symptom Score (PEESS). Secondary end points were proportion experiencing histologic remission (<15 eosinophils per high-power field); change in histologic features (histology scoring system), endoscopic severity (endoscopic reference score), transcriptome (EoE diagnostic panel), and QoL scores; and predictors of remission., Results: Sixty-three patients were randomly assigned to 1FED (n = 38) and 4FED (n = 25). In 4FED versus 1FED, mean PEESS improved -25.0 versus -14.5 (P = .04), but remission rates (41% vs 44%; P = 1.00), histology scoring system (-0.25 vs -0.29; P = .77), endoscopic reference score (-1.10 vs -0.58; P = .47), and QoL scores were similar between groups. The EoE transcriptome normalized in those with histologic response to both diets. Baseline peak eosinophil count predicted remission (odds ratio, 0.975 [95% confidence interval, 0.953-0.999], P = .04; cutoff ≤42 eosinophils per high-power field). The 4FED withdrawal rate (32%) exceeded that of 1FED (11%) (P = .0496)., Conclusions: Although 4FED moderately improved symptoms compared with 1FED, the histologic, endoscopic, QoL, and transcriptomic outcomes were similar in both groups. 1FED is a reasonable first-choice therapy for pediatric EoE, given its effects, tolerability, and relative simplicity., Competing Interests: Disclosure statement Funded through a Patient-Centered Outcomes Research Institute (PCORI) award (CER-1403-11593). The statements presented in this publication are solely the responsibility of the authors and do not necessarily represent the views of PCORI, its board of governors, or its methodology committee. Additional funds for the study were provided by the Division of Allergy and Immunology at Cincinnati Children’s Hospital Medical Center. Disclosure of potential conflict of interest: J. P. Abonia has received payment or honoraria for lectures from Takeda Global Research and Development; has participated on a data safety monitoring board for OctaPharma USA Inc; and has received grants or contracts from Cures Within Reach and Celgene. S. S. Aceves has received consultant fees from Regeneron Pharmaceuticals, AstraZeneca, and Bristol Myers Squibb; has received research funding from Implicit Biosciences; is coinventor of oral viscous budesonide University of California, San Diego, patent Takeda license; and has received educational speaker fees from Sanofi/Genzyme and Regeneron Pharmaceuticals. K. E. Capocelli is employed by and has an equity interest in Alnylam. M. Chehade has served as a consultant for Regeneron Pharmaceuticals, Adare/Ellodi, AstraZeneca, Sanofi, Bristol Myers Squibb, Recludix Pharma, Nexstone Immunology, Allakos, Shire/Takeda, and Phathom; and has received research funding from Regeneron Pharmaceuticals, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, Danone, and Bristol Myers Squibb. M. H. Collins is a consultant for Allakos, Arena Pharmaceuticals, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/BMS, Regeneron Pharmaceuticals, Robarts Clinical Trials Inc/Alimentiv Inc, and Shire/Takeda. E. S. Dellon is a consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; has received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; and has received educational grants from Allakos, Aqilion, Holoclara, and Invea. G. T. Furuta serves as CMO for EnteroTrack LLC; and has received research funding from Arena/Pfizer, Holoclara, and the National Institutes of Health (NIH). S. K. Gupta is a consultant for Abbott, Allakos, Adare Pharmaceuticals, DBV Technologies, Gossamer Bio, QOL Medical, Medscape, Receptos/Celgene, and UpToDate; and has received research support from Shire/Takeda. J. Leung is a consultant for Adare, Eli Lilly, AbbVie, Genzyme, Regeneron, Sanofi, and Shire/Takeda; and has received research funding from Adare, Allakos, Celgene, Regeneron, AstraZeneca, and Shire/Takeda. V. A. Mukkada has received consulting fees from Allakos, Regeneron, Sanofi, and Shire/Takeda; has received honoraria for lectures from the American Gastroenterological Association; and serves on an adjudication board for Alladapt. R. D. Pesek is a consultant for Regeneron Pharmaceuticals. T. Shoda has funding from the NIH and is a coinventor of patents owned by Cincinnati Children’s Hospital Medical Center. J. M. Spergel has received grant support from Regeneron Pharmaceuticals/Sanofi, Novartis, the NIH, and Food Allergy Research and Education; is a consultant for Regeneron Pharmaceuticals, Sanofi, Alladapt, Readysetfood, and ARS Pharmacy; and has received royalties from UpToDate. J. B. Wechsler is a consultant for Allakos, Ellodi, Regeneron Pharmaceuticals, Sanofi/Genzyme, AstraZeneca, Celldex, and Invea Therapeutics; and has received clinical trial/research funding from Allakos, Invea Therapeutics, and Sanofi/Regeneron. M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nexstone One, Santa Ana Bio, EnZen Therapeutics, Bristol Myers Squibb, Astra Zeneca, Pfizer, GlaxoSmith Kline, Sanofi/Regeneron, Revolo Biotherapeutics, and Guidepoint; and has an equity interest in the first nine listed, and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate. M. E. Rothenberg is an inventor of patents owned by Cincinnati Children’s Hospital. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)