Well-differentiated spindle cell liposarcoma represents a rare atypical/low-grade malignant lipogenic neoplasm that has been regarded as a variant of atypical lipomatous tumor. However, well-differentiated spindle cell liposarcoma tends to occur in subcutaneous tissue of the extremities, the trunk, and the head and neck region, contains slightly atypical spindled tumor cells often staining positively for CD34, and lacks an amplification of MDM2 and/or CDK4 in most of the cases analyzed. We studied a series of well-differentiated spindle cell liposarcomas arising in two female and four male patients (age of the patients ranged from 59 to 85 years). The neoplasms arose on the shoulder, the chest wall, the thigh, the lower leg, the back of the hand, and in paratesticular location. The size of the neoplasms ranged from 1.5 to 10 cm (mean: 6.0 cm). All neoplasms were completely excised. The neoplasms were confined to the subcutis in three cases, and in three cases, an infiltration of skeletal muscle was seen. Histologically, the variably cellular neoplasms were composed of atypical lipogenic cells showing variations in size and shape, and spindled tumor cells with slightly enlarged, often hyperchromatic nuclei. Multivacuolated lipoblasts were present in three neoplasms. Focal myxoid stromal changes were seen in three cases. Immunohistochemically, CD34 was at least focally positive in all cases, whereas scattered tumor cells only showed a nuclear expression of MDM2 in two neoplasms. FISH analysis revealed a deletion of the Rb-1 gene in all six cases, whereas no MDM2/CDK4 amplification was identified in all cases tested. Follow-up information was available in four cases (range from 4 to 24 months), and revealed a local recurrence in one case. Although well-differentiated spindle cell liposarcoma and atypical lipomatous tumor behave clinically similar, it can be speculated on the basis of clinicopathologic and molecular findings that well-differentiated spindle cell liposarcoma may constitute an independent entity rather than a morphologic variant of atypical lipomatous tumor, and may represent the atypical/low-grade counterpart of spindle cell lipoma.