Abstract Background: Graft-versus-host disease (GVHD) is a common and undesirable complication of hematopoietic cell transplant (HCT) for non-malignant disorders (NMD). Understanding the incidence and risk factors for GVHD in children with NMD is an important step in developing strategies for its prevention. Study Design: This is a retrospective, registry, study that included children with NMD receiving HCT in 5 centers in Florida between 2010 and 2019. Results: Among 183 patients evaluable for GVHD, acute GVHD (aGVHD) grades I, II, III, and IV were present in 18%, 12.6%, 3.8% and 5.5% of patients, respectively. Limited and extensive chronic GVHD (cGVHD), were observed in 8.7% and 12.6% of patients. Patients with aGVHD grade III/IV had significantly lower 3-year survival rates than those without aGVHD, or those with aGVHD grade I/II (52.9% [95% confidence interval (CI) 34-83] vs. 90.1% [95% CI 84-96], vs. 98.1% [95%CI 95-100], p<0.001). Patients without cGVHD and those with limited and extensive cGVHD had 3-year survival rates of 88.9% [95%CI 84-94], 91.7% [95%CI 77-100], and 84.8% [95%CI 70-100], respectively, log rank p=0.3. Receiving transplant from an HLA-mismatched unrelated donor (MMUD), as compared to a matched related donor (MRD), increased the risk for aGVHD grade III/IV (Odds ratio 10.4 [95% CI 2.5-47.6]). There were no cases of aGVHD grade III/IV among recipients of mismatched related/haploidentical transplants. Conclusions: Grade III/IV aGVHD, which significantly reduced overall survival, was reported in 9.3% of children with NMD receiving HCT. Risk factors included HCT from a MMUD but not mismatched related donors.