Pure erythroid malignancies, such as Di Guglielmo disease (DG), in which the predominant immature elements are proerythroblasts, are excluded from the French-American-British (FAB) classification for acute leukemia and do not fit neatly into any of the categories of myelodysplasia. This retrospective review compares the clinical and laboratory features of DG and erythroleukemia (FAB M6) among 37 cases treated at a single institution over a 7-year period. DG was defined as >30% proerythroblasts and the absence of a myeloblastic component. Clinical and laboratory features were similar in both subtypes. High proportions of secondary leukemias and prior myelodysplastic syndromes (MDS) were noted (M6, 13 of 26 cases; DG, five of 11 cases; p = 0.85). Pancytopenia was common at presentation in both groups [median white blood cells (WBC), 2,600/mm3; HgB, 8.65 gm/dl; platelets, 38,000/microl]. Two-thirds of studied cases had chromosomal abnormalities typified by major karyotypic abnormalities (MAKA) involving three or more chromosomes. Abnormalities involving chromosome 5 and/or 7 occurred in 47% (48% M6 and 45% DG). Both erythroid malignancies carried a poor prognosis (M6, 6.0-month median survival; DG, 4-month survival; p = 0.74). Among those patients choosing aggressive rather than palliative therapy, higher remission rate (80 versus 25%) and survival advantage (11.5 versus 2.5 months) were seen in M6 compared to DG. However, only two long-term survivors exist. The similar clinical and laboratory features, cytogenetic patterns, and poor survival data suggest that the FAB classification schema should be modified to include DG.