Acute promyelocytic leukemia (APL) is genetically characterized by a reciprocal translocation between chromosomes 15 and 17, t(15;17)(q22;q21), which results in the fusion gene PML-RARA. A small proportion of patients with APL have complex or simple variants of this translocation. With conventional cytogenetic methods, these translocations are detected in about 70-90 % of patients, with most of the negative results due to technical problems or cryptic variants. Those masked PML/RARA fusions can be identified by molecular analyses such as reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). We report the case of a 58-year-old man showing morphological, cytochemical, and immunophenotypic features of hypergranular APL (FAB-M4). PML-RARA transcripts were not evident on RT-PCR. Although cytogenetic tests revealed the presence of an apparently balanced translocation t(15;17)(q24;q11) with an abnormal chromosome 12 that characterized a M3 leukemia. This karyotypic interpretation was confirmed by FISH with the use of painting probes of chromosomes 12, 15, and 17 and a PML-RARA dual-color DNA probe. FISH showed a PML-RARA fusion gene on the der(12) instead of the der(15). The patient was treated with an all-trans retinoic acid (ATRA) plus anthracycline-based protocol and achieved complete remission, with no recurrence to date. These results illustrate the usefulness of combining cytogenetics and FISH methods to evidence the PML/RARA fusion gene in cases with morphologic suspicion of APL with variant or cryptic t(15;17).