Background. Anemia is an established negative prognostic factor in myelodysplastic syndromes (MDS), but the relationship between its degree and clinical outcome is poorly defined. We therefore studied the relationship between severity of anemia and outcome in MDS patients. Design and Methods. We studied 840 consecutive patients diagnosed with MDS at the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, and 504 patients seen at the Heinrich-Heine-University Hospital, Dusseldorf, Germany. Hemoglobin levels were monitored longitudinally and analyzed by means of time-dependent Cox proportional hazards regression models. Results. Hemoglobin levels lower than 9 g/dL in males (HR 5.56, P=0.018) and 8 g/dL in females (HR=5.35, P=0.026) were independently related to reduced overall survival, higher risk of non-leukemic death and cardiac death (P<0.001). Severe anemia, defined as a hemoglobin below these thresholds, was found to be as effective as transfusion-dependency in the prognostic assessment. After integrating this definition of severe anemia into the WPSS, time-dependent regression and landmark analyses showed that the refined model was able to identify risk groups with different survivals at any time during the follow-up. Conclusions. Accounting for severity of anemia through the WPSS provides an objective criterion for prognostic assessment and implementation of risk-adapted treatment strategies in MDS patients.