All-trans retinoic acid (ATRA) represents a highly effective treatment for acute promyelocytic leukemia (M3-ANLL). This compound induces the leukemic promyelocytes to differentiate into morphologically and phenotypically mature myeloid cells. The mechanism of action of ATRA is far from fully understood. It has recently been reported that, along with its differentiation activity, ATRA causes apoptosis in the acute promyelocytic leukemia cell line HL-60. In this study we attempted to test whether ATRA is also able to induce apoptosis in fresh leukemic cells from M3-ANLL patients. Our results indicated that although morphological differentiation was detectable in 9/9 M3-ANLL samples after in vitro exposure to ATRA 10(-6) M, the percentage of apoptotic cells in the treated samples did not significantly differ from that obtained in controls (13.1% vs 9.4% respectively, after 8 days exposure). These data suggest that apoptosis does not seem to be the key mechanism by which ATRA exerts its action in M3-ANLL, at least at the blast cell level.