Dedifferentiated liposarcoma (LPS) is a malignant adipocytic neoplasm defined as the transition from well-differentiated LPS to a nonlipogenic sarcoma. Heterologous differentiation is seen in 5% to 10% of dedifferentiated LPS, usually with myogenic or osteo/chondrosarcomatous elements. Adipocytic differentiation in the dedifferentiated component is incompatible with the current definition of dedifferentiated LPS. Pleomorphic LPS is a high-grade sarcoma containing lipoblasts. At least in areas, pleomorphic LPS can be indistinguishable from dedifferentiated LPS, except for the presence of lipoblasts in pleomorphic LPS and well-differentiated LPS areas in dedifferentiated LPS. We evaluated 12 unusual liposarcomas: 11 cases with pleomorphic LPS-like morphology affecting patients with concomitant or previous well-differentiated/dedifferentiated LPS, and 1 case resembling inflammatory “MFH” with scattered lipoblasts. Clinical and histologic features were reviewed. Immunohistochemistry for MDM2 and CDK4 was carried out. Amplification of 12q13 to q15 was studied by FISH analysis of the HMGA2 locus. The tumors arose in the retroperitoneum (7), proximal lower extremity (3), chest wall (1), and neck (1) of 9 males and 3 females (median age 66 y; range 49 to 76). Size ranged from 9 to 32 cm (median 23 cm). In 3 cases, there was an abrupt transition between well-differentiated LPS and sheets of pleomorphic lipoblasts, indistinguishable from pleomorphic LPS. Four cases consisted of otherwise typical dedifferentiated LPS (with adjacent well-differentiated LPS), except for the presence of lipoblasts in the high-grade component. One case contained both nonlipogenic spindle cell areas and an inflammatory “MFH”-like component with numerous admixed lipoblasts. Four cases were composed exclusively of pleomorphic LPS-like areas developing in 1 of the recurrences or metastases of a prior typical dedifferentiated LPS. Two cases also showed heterologous smooth muscle differentiation. MDM2 and CDK4 were positive in both the dedifferentiated LPS and pleomorphic LPS-like components in 12/12 and 11/12 cases, respectively. FISH analysis showed high-level amplification of 12q14.3 in all 8 cases successfully tested. Karyotypes were available for 3 cases and showed ring and giant marker chromosomes. Follow-up, available for 11 patients, ranged from 19 to 196 months (median 36 mo). Seven patients developed local recurrences (multiple in 3), and 3 developed lung metastases. Thus far, 5 patients have died of disease, 3 are alive with recurrent or metastatic disease, and 3 are alive with no evidence of disease. We conclude that dedifferentiated LPS can show lipoblastic differentiation in the high-grade component, resulting in areas indistinguishable from pleomorphic LPS. The available clinical and molecular data support the notion of “homologous” lipoblastic differentiation in dedifferentiated LPS, rather than mixed-type LPS.