CD65s appears when the progenitor antigen CD34 disappears, suggesting that this sialylated carbohydrate antigen marks a turning point in normal myeloid differentiation. We characterized acute myeloid leukemia (AML) with low CD65s expression (CD65s low AML) in 711 patients entered on seven Eastern Cooperative Oncology Group AML treatment trials (1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999). Of those, 198 (28%) qualified as having CD65s low AML. Morphologically, CD65s low AML was more common in FAB subgroups with minimal differentiation, M0/M1 (P ¼ o0.0001). Early precursor antigens CD34, CD117 and terminal transferase were more frequent in CD65s low than CD65s high AML (P ¼ o0.0001). Myeloperoxidase was present in fewer CD65s low myeloblasts, and the more mature myeloid antigens, CD15 and CD11b, were rarely detected (P ¼ o0.0001). Yet, the two diagnoses did not differ in the distribution of cytogenetic prognostic groups or the occurrence of the multidrug-resistance mediator, P-glycoprotein. CD65s low AML patients were significantly older than CD65s high cases (Po0.0001). Furthermore, the incidence of CD65s low cases increased with age, from 20% in patients under the age of 50 years to 67% in patients older than 80 years (Po0.0001). Overall, complete remission (CR) rate and overall survival were comparable in CD65s low and CD65s high AML. However, among patients 455 years of age, CD65s low AML had a decreased CR rate of 33 vs 44% in CD65s high AML (P ¼ 0.055). Thus, CD65s low AML represents immunophenotypically undifferentiated disease and occurs predominantly in older adults. Although not statistically significant, the observed association between low CD65s expression and decreased CR rate only in patients over the age of 55 is intriguing.