Acute myeloid leukemia (AML) with rearrangement of the core-binding factor (CBF) alpha or beta subunit gene has a favorable prognosis, but CD56 expression in CBFalpha-AML is associated with short disease-free survival. A proposed mechanism is overexpression of the multidrug resistance (MDR) protein P-glycoprotein (Pgp). CD56 expression, Pgp expression and function, and expression of the additional MDR proteins multidrug resistance protein-1 (MRP-1), lung resistance protein (LRP) and breast cancer resistance protein (BCRP) were studied in pretreatment blasts from 25 CBF-AML patients. CD56 expression was frequent in CBFalpha but rare in CBFbeta, and Pgp expression and function were frequent in both subtypes. CD56 expression did not correlate with Pgp expression or function, nor with expression of the other MDR proteins. Treatment failure associated with CD56 expression in CBFalpha-AML is not likely attributable to Pgp.