6555 Background: TBI/Cy is a commonly used conditioning regimen prior to allogeneic stem cell transplant (SCT). Chemotherapy only regimens, mostly containing busulfan, have been shown to be effective and less toxic in patients with myeloid malignancies. Here, we present the largest reported experience with a non-busulfan myeloablative chemotherapy regimen of TT/Cy in myeloid malignancy patients undergoing allogeneic SCT and compare outcomes with TBI/Cy. Methods: Patients with myeloid malignancies receiving allogeneic SCT at Indiana University from 2007-2020 were included. TT/Cy consisted of TT 15 mg/kg and Cy 120 mg/kg. TBI/Cy consisted of 13.2 Gy in 8 fractions and Cy 3600 mg/m2. The primary endpoint was overall survival (OS). Secondary endpoints included relapse-free survival (RFS), engraftment, and toxicities within the first 100 days. Median follow up for surviving patients is 2,046 (range 816-5,572) days. Results: 225 patients with AML (n=160), CML (n=45), and MDS (n=30) of median age 44 (range 19-59 years) received conditioning with TT/Cy (n=159) or TBI/Cy (n=66). Baseline characteristics were similar. For TT/Cy patients, the median OS was not reached, and 4-year OS was 57.2% (95% confidence interval [CI], 49.2-65.2%), which was significantly better than with TBI/Cy, with median OS 373 days and 4-year OS 33.9% (95% CI, 22.3-45.5%; p<.001). Similarly, for TT/Cy patients, the median RFS was not reached and 4-year RFS was 59.2% (95% CI, 52-67.2%), significantly better than median RFS of 341 days and 4-year RFS 35.2% (95% CI, 23.7-46.9%; p<.001) for recipients of TBI/Cy. On multivariable analysis adjusting for age, sex, diagnosis, disease risk, comorbidity index (HCI), and degree of stem cell source, TT/Cy had significantly lower risk of death (HR 0.44, 95% CI, 0.30-0.65; p<.001) together with female sex (p=.03) and lower HCI (p=.046). As shown in the Table summarizing secondary endpoints, TBI/Cy was associated with significantly higher rates of mucositis, sinusoidal obstruction syndrome (SOS), TPN usage, multiorgan failure, and length of stay of primary admission. Conclusions: TT/Cy is an efficacious regimen for patients with myeloid malignancies undergoing myeloablative allogeneic SCT with less toxicity and improved RFS and OS compared with TBI/Cy. TT/Cy should be compared to other non-TBI containing busulfan-based regimens. [Table: see text]