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Objectives: The optimal approach for resuscitation in septic shock remains unclear despite multiple randomized controlled trials (RCTs). Our objective was to investigate whether previously uncharacterized variation across individuals in their response to resuscitation strategies may contribute to conflicting average treatment effects in prior RCTs., Design: We randomly split study sites from the Australian Resuscitation of Sepsis Evaluation (ARISE) and Protocolized Care for Early Septic Shock (ProCESS) trials into derivation and validation cohorts. We trained machine learning models to predict individual absolute risk differences (iARDs) in 90-day mortality in derivation cohorts and tested for heterogeneity of treatment effect (HTE) in validation cohorts and swapped these cohorts in sensitivity analyses. We fit the best-performing model in a combined dataset to explore roles of patient characteristics and individual components of early goal-directed therapy (EGDT) to determine treatment responses., Setting: Eighty-one sites in Australia, New Zealand, Hong Kong, Finland, Republic of Ireland, and the United States., Patients: Adult patients presenting to the emergency department with severe sepsis or septic shock., Interventions: EGDT vs. usual care., Measurements and Main Results: A local-linear random forest model performed best in predicting iARDs. In the validation cohort, HTE was confirmed, evidenced by an interaction between iARD prediction and treatment ( p < 0.001). When patients were grouped based on predicted iARDs, treatment response increased from the lowest to the highest quintiles (absolute risk difference [95% CI], -8% [-19% to 4%] and relative risk reduction, 1.34 [0.89-2.01] in quintile 1 suggesting harm from EGDT, and 12% [1-23%] and 0.64 [0.42-0.96] in quintile 5 suggesting benefit). Sensitivity analyses showed similar findings. Pre-intervention albumin contributed the most to HTE. Analyses of individual EGDT components were inconclusive., Conclusions: Treatment response to EGDT varied across patients in two multicenter RCTs with large benefits for some patients while others were harmed. Patient characteristics, including albumin, were most important in identifying HTE., Competing Interests: Drs. Shah’s, Talisa’s, Chang’s, Tang’s, Cooper’s, Angus’s, and Yende’s institutions received funding from the National Institutes of Health (NIH; GM141081). Dr. Shah’s institution received funding from the NIH (K23GM122069, R21HL168070). Dr. Shah, Dr. Talisa, Dr. Chang, Dr. Triantafyllou, Dr. Tang, Mr. Kennedy, Dr. Cooper, Dr. Yealy, Dr. Seymour, Dr. Angus, and Dr. Yende received support for article research from the NIH. Dr. Talisa disclosed the study was supported by the NIH (UL1TR001857; S10OD028483). Dr. Triantafyllou, Mr. Kennedy, Dr. Cooper, and Dr. Seymour’s institutions received funding from the NIH (R01HL164835). Dr. Mayr’s institution received funding from the NIH (K23GM132688); he disclosed government work; and he received personal fees from Baxter for serving on a racial disparities advisory board outside the submitted work. Dr. Higgins’ institution received funding from the National Health and Medical Research Council (NHMRC) (GNT2008447); she received support for article research from the NHMRC. Mr. Mouncey’s institution received funding from the National Institute for Health and Care Research Health Technology Assessment program; he received support for article research from the National Institute for Health and Care Research. Mr. Kennedy’s and Dr. Seymour’s institutions received funding from the NIH (R21GM144851). Mr. Kennedy’s, Dr. Cooper’s, and Dr. Seymour’s institution received funding from the National Institute for General Medical Sciences (R35GM119519). Dr. Yealy’s institution received funding from the NIH. Dr. Seymour received funding from Beckman Coulter and Octapharma. Dr. Angus received funding from AM-Pharma and Abionyx. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)