Rearrangements of the short arm of chromosome 12 are among the most common aberrations found in hematologic malignancies, including myelodysplastic syndromes, acute myelocytic leukemias, acute lymphoblastic leukemias, and non-Hodgkin lymphomas. We report on a group of 46 patients with a variety of myelocytic and lymphoid malignancies, all with an inversion of chromosome 12. Both pericentric and paracentric inversions occurred. The identified hotspots for breakage were p13 and q24. These correspond to gene-rich areas of known chromosome instability. The inv(12) is difficult to detect and may be misinterpreted as a partial deletion by routine cytogenetics. Fluorescence in situ hybridization studies revised the G-banding interpretations of a deleted 12p in some cases to an inversion. The inv(12) may occur as the sole abnormality in both myelocytic and lymphoid malignancies, suggesting lineage promiscuity as seen with MLL and ETV6 gene disruptions. The majority of patients with the inv(12) had complex karyotypic changes that predicted a poor prognosis. Of the 24 patients with known clinical follow-up, many were refractory to chemotherapy and overall survival was short.