Acute promyelocytic leukemia (APL) is characterized by a specific translocation (15;17)(q22;q21), resulting in the formation of PML/RARalpha chimeric transcripts. We report two female patients with PML/RARalpha-positive classical APL, whose leukemic cells expressed a variant translocation, t(5;15)(q13;q22) and t(15;17)(q22;p13), respectively. Both translocations were confirmed by whole chromosome painting which revealed no apparent involvement of 17q. A two-color fluorescence in situ hybridization with a 5' PML and a 3' RARalpha probe showed, in both cases, the presence of a PML-RARalpha fusion gene, on the der(15)t(5;15) long arm, and on the der(17)t(15;17) short arm, respectively. These two complex rearrangements resulted most probably from a two-step mechanism: (1) a submicroscopic insertion into 15q of a 17q segment including the 3' part of the RARalpha gene; (2) a reciprocal translocation between der(15) and a variable chromosome arm, with a breakpoint distal and proximal to RARalpha insertion in the case of t(5;15) and t(15;17), respectively. Molecular and prognosis significance of these variant translocations are discussed.