BACKGROUND AND OBJECTIVES: Acute promyelocytic leukemia (APL) is characterized by leukemic cells blocked at the promyelocytic stage of granulocytic differentiation. To date, it is still not clear whether CD34 expression identifies a subset of APL patients with peculiar characteristics. We, therefore, conducted a detailed analysis of CD34 expression at diagnosis in 136 adults with de novo APL. DESIGN AND METHODS: We investigated 136 newly diagnosed APL patients from four Italian Institutions. All 136 cases were tested for CD34 and CD2 expression: 124 (91%) cases were classified as hypergranular (M3) and 12 (9%) as the hyporgranular M3 variant (M3v). The parameters considered were white blood cell (WBC) and platelet counts, hemoglobin levels, percentage of peripheral blood leukemic promyelocytes (PBLP), CD15, CD56 and HLA-DR expression, and the PML/RARalpha isoform, to assess their relationship with CD34 and CD2 expression. RESULTS: CD34 expression was associated with the M3v subtype and higher proportion of HLA-DR+ and CD2+ cases. Moreover, compared with CD34- APL patients, CD34+ APL patients had a significantly higher percentage of PBLP at presentation, were more frequently female and had a higher proportion of bcr3 expression. Among the 136 APL cases, 24 (17.6%) and 80 (58.8%) were identified as CD34+CD2+ and CD34-CD2-, respectively. The two groups showed statistically significant differences in terms of M3vfrequency, WBC and platelet counts, percentage of PBLP, and bcr3 expression. Moreover, the CD34+CD2+ group showed a higher proportion of CD34+ and bcr3 isoforms compared to the M3v cases. There were no differences between the two groups in terms of complete remission, overall survival and disease-free survival. INTERPRETATION AND CONCLUSIONS: Our findings suggest that immunophenotypic analysis can distinguish a subset of APL patients with different biological characteristics.