Background: AML arising from previously treated myeloid neoplasm (tsAML) is considered a distinct category of sAML less responsive to therapy. AML from MDS (MDS-sAML) formerly treated with HMA is the most common entity in this category but has not been independently studied. We determined the impact of prior HMA therapy on MDS-sAML survival. Methods: Patients (pts) with MDS were identified in SEER-Medicare 2007-2017 by ICD-O-3 histology codes. MDS-sAML was confirmed by at least 2 AML ICD codes. Established algorithms were used to define MDS risk group, Charlson comorbid index (CCI), transfusion dependence and HMA therapy. We used logistic regression to test factors associated with HMA therapy before transformation, and multivariable Cox regression with propensity score matching (PSM) for survival analysis after transformation. Results: We included 1,871 pts with MDS-sAML, of which 1,151 (61.5%) received at least 1 HMA cycle before AML transformation and 826 (44.1%) had sustained HMA therapy (4 or more cycles). Preceding MDS was of low, intermediate, and high risk in 6.2%, 61.9%, and 31.9% pts, respectively. Younger age (odds ratio [OR] = 1.6, 95% confidence interval [95 CI]: 1.3-1.9), lower CI (OR = 1.4, 95 CI: 1.2-1.5), higher MDS risk (OR = 2.3, 95 CI: 2.3-2.8), and RBC (OR = 1.3, 95 CI: 1.2-1.5) and platelet transfusion dependence (OR = 3.4, 95 CI: 2.8-4.0), were associated with pre-AML HMA use (all respective p < 0.05). Median OS after AML transformation was 3.3 months and was longer in pts previously treated with HMA, particularly ≥4 cycles (4 vs 2 months, p < 0.01). The 1:1 matched HMA and non-HMA groups were similar for all variables listed in the table. In the PSM cohort, prior HMA therapy was associated with 22% lower hazard of death in MDS-sAML (hazard ratio [HR] = 0.78, 95 CI: 0.7-0.88, p < 0.01). Traditional Cox regression adjusted for age, sex, race, MDS risk, CCI, RBC and platelet transfusion dependence, confirmed these results (HR = 0.76, 95 CI: 0.68-0.84, p < 0.01). The point estimate of the association of HMA therapy with lower risk of death was lower in pts who received ≥4 cycles (HR = 0.62, 95 CI: 0.56-0.69, p < 0.01). Conclusions: Real-world survival of MDS-sAML pts is dismal but HMA exposure preceding AML transformation is associated with longer survival. Further studies are needed to determine whether this reflects the impact of HMA on subsequent AML biology or residual confounding.