We describe an elderly patient with acute promyelocytic leukemia (APL), whose leukemic cells expressed CD56 antigen at relapse but not at diagnosis. Chromosome analysis revealed that blasts with t(8;15;17)(q24.1;q22;q11.2) increased from 4 of 20 cells (20%) at first relapse to 10 of 14 cells (71.4%) at second relapse. In addition, the positivity for CD56 expression on blasts judged by flow cytometric analysis using CD45 blast gating was also increased from 14.2% at first relapse to 75% at second relapse. Although conventional chemotherapy was performed for the initial disease and the first relapse, relapse developed again. Therefore, three courses of intensive postremission chemotherapy including concurrent administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) with cytarabine were performed after achievement of complete remission (CR) by the treatment with all-trans-retinoic acid (ATRA). Although PML-RARαmRNA was not detectable by reverse transcription polymerase chain reaction (RT-PCR), a third relapse occurred. This case demonstrated clonal evolution from a CD56− to a CD56+ blast population and provided further support for the suggestion that CD56 expression might be an unfavorable prognostic factor in t(15;17) APL. Am. J. Hematol. 69:59-63, 2002. © 2002 Wiley-Liss, Inc.