Background: The AZA-001 trial has shown a survival advantage for patients with high-risk MDS treated with HMA as compared to IC. However, this study was conducted mainly in an older population. Methods: We retrospectively analyzed the characteristics and outcomes of patients with MDS, younger than 60 years of age, with ≥ 10% bone marrow blasts who received frontline treatment with HMA or anthracycline-cytarabine-based IC at our institution between 10/1993 and 12/2017. Results: One-hundred and six patients were included in the study, 57 treated with HMA and 49 with IC. Use of IC was associated with shorter time to response (1 vs 2 months; p < 0.001) and higher overall response rate (ORR; 82% vs 60%, p = 0.02). On univariate analysis (UA) age younger than 50 (p = 0.03) and use of IC (p = 0.02) were associated with ORR, but on multivariate analysis (MVA) only use of IC maintained its association (OR 4.3, 95% CI 2-9.1; p < 0.001). Rates of treatment discontinuation secondary to early death or toxicity were comparable; 31% of patients on HMA and 33% on IC proceeded to stem cell transplant (SCT). After a median follow-up of 15 months (range, 1-178 months), 38 (51%) out of 74 patients lost their response, and median response duration (RD) was 19 months (range, 1-166 months). Factors associated with longer RD on UA were lack of unfavorable cytogenetics (p = 0.04), consolidation with SCT in first remission (p = 0.009) and use of IC (p = 0.03); on MVA, use of IC maintained its association (HR 2.9, 95% CI 1.4-5.8, p = 0.03). Eight (8%) patients transformed to acute myeloid leukemia during frontline treatment, 7 (12%) on HMA and 1 (2%) on IC (p = 0.07). At most recent follow-up, 65 (61%) patients died, median overall survival was 21 months (range, 1-178 months) and was significantly longer for patients treated with IC (43 vs 15 months; p = 0.05). Conclusions: IC is more effective than HMA for younger patients with MDS and bone marrow blasts ≥ 10%, irrespective of other baseline characteristics. Strategies combining targeted agents with either HMA or IC should be investigated, to determine whether this advantage will be maintained.