Despite the success of the current therapy for patients with acute promyelocytic leukemia (APL), relapse occurs in up to 30% of patients. The characteristics of relapsed APL are not well described. We evaluated a group of APL cases at relapse and compared the clinicopathologic, immunophenotypic, molecular, and cytogenetic findings with those at initial diagnosis. From a group of 207 patients with APL, in 38 patients morphologic evidence of relapse developed. In 30 patients relapse was isolated to bone marrow, and 8 had extramedullary disease. Blasts were morphologically stable in 37 patients. Changes in the immunophenotypic profile were common, the most frequent being gain of CD34, HLA-DR, or CD33 and attenuation or loss of CD13. Cytogenetic changes were common at relapse. The size of the PML-RARalpha fusion transcript was invariable. We conclude that changes in the immunophenotype and cytogenetic evidence of clonal evolution are common in APL at the time of relapse.