Most well-differentiated liposarcomas can be readily distinguished from lipomas on histologic grounds alone. However, occasional retroperitoneal lipomatous tumors show no cytologic atypia. To determine whether these tumors are well-differentiated liposarcomas devoid of cytologic atypia or lipomas was the major aim of this investigation. We comprehensively and prospectively studied 19 retroperitoneal adipocytic tumors devoid of cytologic atypia at the cytogenetic and molecular genetic levels. Median patient age was 56 years (range: 36 to 78 y). Median tumor size was 21 cm (range: 8 to 46 cm) and the median weight was 1127 g (range: 173 to 2440 g). All tumors were well-circumscribed and showed no cytologic atypia. Standard cytogenetic analysis demonstrated rearrangements of 12q15 in 4 (of 7) cases. None showed ring or giant marker chromosomes. Fluorescence in situ hybridization failed to identify amplification of MDM2, carboxypeptidase M(CPM), SAS, CDK4, DDIT3, or HMGA2 in all cases. HMGA2 rearrangement was observed in 8 (of 19) cases (42%) and was more common in larger tumors (P=0.046). HMGA2-LPP fusion was seen in only 1 case. All tumors were completely excised. Follow-up information was available from 10 cases (median, 6 mo; range: 1 to 58 mo). No tumor recurred or metastasized. In contrast, a control group of 20 well-differentiated liposarcomas diagnosed during the same time period (matched per year of diagnosis) showed 4 instances of local recurrence. We conclude that this group of retroperitoneal lipomatous tumors shows clinico-pathologic and genetic features more akin to lipomas than well-differentiated liposarcomas. Owing to their apparent rarity, additional studies are necessary to more fully understand their natural biology in this anatomic location.