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Flow cytometry (FCM) is a co-criterion in myelodysplastic neoplasms (MDS) diagnostics, currently not used for prognostication. This study aimed to develop an FCM-score predicting overall survival (OS) in MDS to improve early clinical patient prognostication. FCM of bone marrow samples was performed for diagnostic purposes in 509 therapy-naïve MDS patients and 77 healthy donors. The following methodology was used: (1) uni- and multivariate Cox proportional hazards regression and Kaplan-Meier curves for OS to assess FCM-parameters' prognostic value; (2) receiver operating characteristic (ROC) curves to test the prognostic superiority of FCM-parameters versus established FCM-scores and clinical risk-scores; and (3) development of a FCM-prognostic score (FCM-PS) based on six FCM-parameters with independent prognostic impact. The final FCM-PS included aberrancies of progenitor cells (increased CD45 mean fluorescence intensity [MFI]-ratio of lymphocytes and myeloid progenitor cells, decreased % of lymphatic progenitor cells), granulopoiesis (increased CD33 MFI, decreased sideward scatter [SSC]-ratio of granulopoiesis and lymphocytes), lymphocytes (increased % of B-lymphocytes), and plasmacytoid dendritic cells (increased %). FCM-PS outperformed established scores for OS (hazard ratio [HR] 4.08 [95% CI 2.54-6.55] vs. Ogata-score: 2.44 [1.61-3.70], International Prognostic Scoring System-Revised [IPSS-R]: 2.37 [1.61-3.49], International Prognostic Scoring System-Molecular [IPSS-M]: 0.816 [0.303-2.196]). Patients in the FCM-PS low score category showed significantly better OS (P < 0.0001). Further, FCM-PS allowed discrimination within IPSS-R area under the curve [AUC]: 0.70 vs. 0.62) and IPSS-M (AUC: 0.75 vs. 0.48) subgroups. Validation of the prognostic FCM-PS in an independent patient cohort confirmed good discrimination performance (AUC: 0.70). We introduce a unique, easy-to-use prognostic FCM-PS score (panel: CD45/CD34/CD117/CD33/CD19/CD123/HLA-DR) for OS in MDS, allowing refined risk stratification for IPSS-R subgroups.