The International Prognostic Scoring System (IPSS) was recently revised (IPSS-R) under the auspices of the MDS Foundation as a collaborative international effort to refine its prognostic power. Our purpose was to externally validate this new risk model using a large single-institution cohort, determine its prognostic power in patients receiving active treatment, and explore its utility in guiding therapeutic decisions. Data were collected retrospectively from our myelodysplastic syndrome (MDS) database and verified by chart review. Of the 1088 patients with data available, 152 (14%), 353 (32%), 237 (22%), 190 (18%), and 156 (14%) patients were classified as very low, low, intermediate, high, and very high risk, respectively, with median overall survival (OS) of 90 (95%CI 71-109), 54 (95%CI 50-59), 34 (95%CI 26-43), 21 (95%CI 17-25), and 13 months (95%CI 11-15), respectively (P<0.005). We found that the IPSS-R further refined prognostic discrimination in all IPSS risk categories, particularly in the intermediate-1 and -2 groups. Among high and very-high IPSS-R patients receiving azacitidine, OS was significantly improved versus patients not receiving azacitidine, with corresponding median OS of 25 versus 18 months (P=0.023) and 15 versus 9 months (P=0.005), respectively. Similarly, patients with IPSS-R high and very-high risk disease who underwent allogeneic hematopoietic stem cell transplantation had significantly improved OS versus non-transplant approaches (P<0.005). High and very-high IPSS-R patients derived a survival advantage from disease-modifying therapies. Our data validate the prognostic value of the proposed IPSS-R and show that its refined IPSS prognostic discrimination can be applied to actively treated patients.