Seventy-three patients with acute leukemias or chronic myelogenous leukemias in blast crisis were evaluated as to the susceptibility of their leukemic cells to differentiation induction by a chemical agent, 12-O-tetradecanoyl phorbol-13-acetate (TPA). Leukemic cells of myeloid origin treated with TPA showed monocyte-macrophage-lineage differentiation morphologically and functionally, whereas those of lymphoid origin did not. We applied these differentiation phenomena for the clinical diagnosis of three leukemia cases in whom it was difficult to determine whether the leukemic cells were of non-lymphoid or lymphoid origin, although all the regular diagnostic procedures available had been performed. We successfully diagnosed these three cases by utilizing the above differentiation phenomena. Furthermore, this technique was clinically beneficial as to the choice of adequate chemotherapy in each of these leukemia cases. These findings confirm that the responsiveness to TPA of leukemic cells is of clinical usefulness for the definite diagnosis of acute leukemias.