Myxoid liposarcomas (MLSs) with extensive lipoma-like changes (MLSLC) are rare, and it is often difficult to distinguish them from well-differentiated liposarcoma (LS)/dedifferentiated LS (WDLS/DDLS) with myxoid changes. For the characterization of these neoplasms, we studied 8 MLSLCs, 11 ordinary MLSs, 4 WDLSs, and 6 DDLSs. Cytogenetically, MLSLC and ordinary MLS were characterized by t(12;16)(q13;p11) and FUS-DDIT3 fusion gene, whereas WDLS/DDLS lacked the fusion gene but possessed giant marker/ring chromosomes. Both lipoma-like and myxoid components of the same MLSLC exhibited the identical FUS-DDIT3, as confirmed by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemically, MDM2 and CDK4 were positive in WDLS/DDLS but negative in MLSLC and ordinary MLS. PPARγ, C/EBPα, adipophilin, and perilipin were found in each type of LS. Adipophilin was expressed chiefly in tiny fat droplets of immature lipoblasts, whereas perilipin showed a strong positive staining in large fat vacuoles of signet ring and multivacuolated lipoblasts. The Ki-67 labeling index was lower in the lipoma-like component of MLSLC when compared with the myxoid component of the same tumors as well as ordinary MLS (p < 0.001). When compared with ordinary MLS, MLSLC may be less aggressive in clinical behavior (rare recurrences or metastases) after a wide surgical excision. In conclusion, the distinction between MLSLC and WDLS/DDLS is important, because of the differences of molecular cytogenetic features as well as clinical behaviors between these distinct sarcomas presenting similar morphologic features. In addition, the combined immunohistochemical detection of adipophilin and perilipin may provide a useful ancillary tool for identification of lipoblastic cells in soft tissue sarcomas.