We have conducted four prospective multicenter studies for acute promyelocytic leukemia (APL) using oral 45 mg/m2 all-trans retinoic acid (ATRA) daily. The first three studies were for relapsed/refractory APL, and the fourth study for newly diagnosed APL. In the first study with ATRA alone, 18 (82%) of 22 evaluable patients achieved complete remission (CR). Initial peripheral leukemia cell counts were significantly less in the CR cases (p < 0.01); < 100/microliters in 17 of 18 CR cases, and > or = 200/microliters in all failure cases. In the second study, if initial leukemia cell counts were more than 200/microliters, chemotherapy with daunorubicin and behenoyl cytarabine was first given, and then ATRA was started. Of 42 evaluable patients, 36 (86%) achieved CR. In the third study, if initial leukemia cell counts were more than 200/microliters, chemotherapy was concomitantly given with ATRA, and if during the ATRA therapy leukemia cell counts became more than 1000/microliters, chemotherapy was added. Of 46 evaluable patients, 36 (78%) achieved CR. Patients achieving CR received standard consolidation and maintenance chemotherapy, and the 29-month predicted disease-free survival (DFS) rate is 72% for 41 cases achieving their first CR with ATRA, and 20% for 49 cases achieving their second CR with ATRA. In the fourth study for newly diagnosed APL, if leukocyte counts were more than 3000/microliters, chemotherapy was concomitantly given with ATRA, and if during the ATRA therapy leukemia cell counts became more than 1000/microliters, chemotherapy was added. Of 109 evaluable patients, 97 (89%) achieved CR, and the 19-month predicted event-free survival rate for all patients is 78%, and the DFS rate is 88% for 97 cases achieving CR. ATRA produces a high CR rate in both relapsed/refractory and newly diagnosed APL, and should be incorporated in the first-line therapy of this disease.