Pleomorphic liposarcoma (PL) is an undifferentiated pleomorphic sarcoma containing pleomorphic lipoblasts. PL almost always arises de novo without an associated low-grade precursor lesion [eg, well-differentiated liposarcoma (WDL)]. We have, however, observed rare cases of PL, which arose in association with WDL and have studied these cases to define their clinicopathologic features and their nosologic relationship to other forms of liposarcoma. Cases were retrieved from our consultation archives and from review of cases treated surgically at Mayo Clinic. Selected tumors were tested for MDM2/CPM amplification by fluorescence in situ hybridization when tumor blocks were available. Twelve tumors were identified, occurring in 7 men and 5 women (mean age 59 y, range: 35-84 y). Sites of origin included the retroperitoneum (7), scrotum (2), buttock (2), and abdominal cavity (1). Tumors consisted predominately of typical WDL, with an "abrupt" transition to pleomorphic spindle cell sarcoma containing pleomorphic lipoblasts. MDM2/CPM amplification was present in 10 of 11 (91%) cases, all of which consisted chiefly of PL in the studied blocks. Follow-up information was available for 7 of 7 patients with a postresection interval of >12 months (range: 14-165 mo, mean 44 mo). Four of these 7 patients are currently alive without disease (mean follow-up duration, 38 mo). Of the remaining 3 patients, 1 died of progressive disease 29 months after diagnosis, 1 suffered lung metastases and local recurrence 60 and 84 months after diagnosis, respectively, and was alive with unresectable disease 165 months after diagnosis, and 1 died 14 months after diagnosis, of unrelated causes. The 5 patients with a postoperative follow-up duration of <12 months are without evidence of disease. We conclude that PL arising in WDL is a rare phenomenon. The presence of MDM2/CPM amplification in the PL component of mixed WDL/PL suggests that a subset of PL may arise through tumor progression of WDL or may represent a "transitional" or partially differentiated step toward classic DL.