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Allogeneic hematopoietic cell transplantation (HCT) offers a potentially curative therapy in patients with hematologic malignancies; however, nonrelapse mortality (NRM) remains a concern. Strategies to improve neutrophil recovery and immune reconstitution are needed to decrease NRM. Murine models of allogeneic HCT suggest that fractionated hematopoietic progenitor cell (HPC) infusion may improve engraftment through improved access of HPCs to a viable hematopoietic niche. The primary objective of the present study was to determine the impact of fractionated infusion versus unfractionated (bulk) infusion of HPCs on the time to achieve neutrophil engraftment. Secondary objectives included the effect of fractionated versus bulk infusion of HPCs on platelet engraftment, immune reconstitution, the incidence of acute graft-versus-host disease (GVHD) grade II-IV, NRM, and overall survival (OS). In this randomized phase 2 study, patients with hematologic malignancies undergoing allogeneic HCT were randomized to receive HPC infusion as a bulk (bulk arm) or in fractions (fractionated arm): 4 × 10 6 CD34 + cells/kg recipient weight infused on day 0, with the remaining HPCs CD34 + cell-selected then infused in equally distributed aliquots on days 2, 4, and 6 post-HCT. Randomization was stratified by type of transplant, unmodified (i.e. T cell-replete graft) versus CD34 + cell-selected (T cell-depleted graft). Patients whose donor failed to collect at least 7 × 10 6 CD34 + cells/kg of recipient weight received bulk HPC infusions regardless of randomization, for safety. These patients continued the HCT process on study but were replaced until each arm reached the prespecified accrual target. Per protocol, these patients were not included in this modified intention-to-treat analysis. A total of 116 patients were enrolled. Donors of 42 patients failed to mobilize the minimum CD34 + cell dose (7 × 10 6 cells/kg recipient weight) and were excluded from the analysis. The 74 evaluable patients included 38 randomized to the bulk arm and 36 randomized to the fractionated arm. All patients engrafted. The median time to an absolute neutrophil count of ≥0.5 × 10 9 /L was 11 days on both arms. The day +180 median CD4 + cell count was 179 cells/µL in the bulk arm and 111 cells/µL in the fractionated arm (P = .779). The cumulative incidence of grade II-IV acute GVHD on post-transplant day +100 was 32% in the bulk arm and 17% in the fractionated arm (P = .131). Two patients in the bulk arm, but none in the fractionated arm, experienced grade III-IV GVHD. The 4-year OS was 60% in the bulk arm and 62% in the fractionated arm (P = .414), whereas the 4-year cumulative incidences of NRM and relapse were similar in the 2 arms. Fractionated infusion of HPCs in allogeneic HCT recipients did not impact neutrophil or CD4 + cell recovery, NRM, relapse, or OS when compared with bulk HPC infusion. We also observed that with current mobilization techniques, it was unlikely that more than 60% of healthy donors would be able to collect >7 × 10 6 CD34 + cells/kg recipient weight for adult recipients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., Competing Interests: Conflict of interest statement D.M.P. has served on advisory boards for Generon, Kadmon, CareDx, and Ceramedix and as a paid consultant for Guidepoint Global Advisors and Gerson Lehrman Group. M.A.P. reports honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Celgene, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Novartis, Nektar Therapeutics, Omeros, and Takeda; serves on data safety and monitoring boards for Cidara Therapeutics, Servier, and Medigene and the scientific advisory board of NexImmune; has received research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, and Novartis; and serves in a volunteer capacity as a member of the Board of Directors of Be The Match (National Marrow Donor Program), as well as on the CIBMTR Cellular Immunotherapy Data Resource Executive Committee. S.A.G. has received research funding from Actinium Pharma, Celgene, Bristol-Myers Squibb, Sanofi, Amgen, Pfizer, Jensen, and Takeda and serves as a research consultant for Kite Pharma and on advisory boards of Actinium, Celgene, Bristol-Myers Squibb, Sanofi, Amgen, Pfizer, GSK, Jazz, Jensen, and Omeros. B.G. reports research funding for a clinical trial from Actinium Pharma. The other authors have no conflicts of interest to report., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)