Therapy-related myeloid neoplasms (t-MNs) include therapy-related acute myeloid leukemia (t-AML) and therapy-related myelodysplastic syndromes (t-MDS), arising from exposure to cytotoxic chemotherapy and/or radiation therapy used to treat prior malignancies. We conducted a retrospective study in a large cohort of patients at Gustave-Roussy Institute, over the period extending from January 1st, 1995 to June 30th, 2018. We used the 2010 ELN prognostic classifications for AML and or IPSS for MDS. In all, 404 patients with t-MN were referred to our institution, including 204 cases of t-AML and 200 cases of t-MDS. Based on the ELN 2010 classification 43%, 22% and 20% of t-AML were classified as adverse, intermediate (I/II) and favorable, respectively. Based on the IPSS classification, 72% of t-MDS were considered as intermediate-2/high and 28% as low/intermediate-1 risk. The median overall survival (OS) was 11.9 months for both t-AML and t-MDS (95% CI: 8.5–14.2 for t-AML and 9.3–14.1 for t-MDS), but long-term survival was mainly demonstrated in t-AML patients (5 years OS 24.6% [19–31.3] in t-AML vs. 10.6% [6.8–16.3] in t-MDS). In multivariate analysis for t-AML, intensive therapy (HR [95%CI]: 0.26 [0.15–0.46]), adverse ELN 2010 risk (1.57 [1.03–2.39]), cancer disease status (2.65 [1.53–4.57]) and performance status>1 (2.69 [1.72–4.14]) were a powerful markers of OS. For t-MDS, only intermediate 2/high IPSS score (3.11 [2.06–4.79]) and Performance Status>1 (3.13 [2.05–4.71]) remained independent markers of OS. Despite some benefit from intensive therapies in selected t-MN cases, survival remains limited, particularly when adverse disease features or active malignancies are present.