Engraftment syndrome (ES), characterized by fever, rash, pulmonary edema, weight gain, liver and renal dysfunction, and/or encephalopathy, occurs at the time of neutrophil recovery following hematopoietic cell transplantation (HCT). In this study, we evaluated the incidence, clinical features, risk factors, and outcomes of ES in children and adults undergoing first-time allogeneic HCT. Among 927 patients, 119 (13%) developed ES at a median of 10 days (interquartile range 9-12) post-HCT. ES patients experienced significantly higher cumulative incidence of grade 2-4 acute GVHD at day 100 (75% vs. 34%, p<0.001) and higher non-relapse mortality at 2 years (38% vs. 19%, p<0.001), compared with non-ES patients, resulting in lower overall survival at 2 years (38% vs. 54%, p<0.001). There was no significant difference in relapse at 2 years (26% vs. 31%, p=0.772). ST2, IL2Rα, and TNFR1 plasma biomarker levels were significantly elevated in ES patients. Our results illustrate the clinical significance and prognostic impact of ES on allogeneic HCT outcomes. Despite early recognition of the syndrome and prompt institution of corticosteroid therapy, outcomes in ES patients were uniformly poor. This study suggests the need for a prospective approach of collecting clinical features combined with correlative laboratory analyses to better characterize ES.