Distinguishing dedifferentiated liposarcoma (DDLPS) from other high-grade spindle and pleomorphic sarcomas is important because of better prognosis in case of DDLPS. MDM2 amplification, a genetic abnormality of well-differentiated liposarcoma, is known to be present not only in DDLPS, but also in some other sarcomas. To differentiate DDLPS, we investigated MDM2 amplification and expression in high-grade spindle sarcomas. Eighty-five cases of nonlipogenic high-grade sarcomas, diagnosed between 2008 and 2011, were investigated. Tissue microarray, immunohistochemistry, and fluorescence in situ hybridization for MDM2 were performed. Forty-one of 85 cases (48.2%) showed MDM2 amplification and expression. Cases of MDM2 amplification were reclassified based on histology, immunophenotype, and clinical data. Thirty-nine of 41 cases, including those originally diagnosed as DDLPS (n=30), undifferentiated pleomorphic sarcoma (n=7), myxofibrosarcoma (n=1), and pleomorphic liposarcoma (n=1) could be reclassified as DDLPS. In addition, MDM2 immunohistochemistry and MDM2 fluorescence in situ hybridization showed an excellent correlation (P<0.001, sensitivity 92.7%, specificity 100%). MDM2 amplification and expression are potentially very useful in distinguishing between DDLPS and other undifferentiated high-grade spindle and pleomorphic sarcomas, even though a few other sarcomas also showed MDM2 amplification and expression.