Differentiating benign from malignant fatty tumours has always been very difficult for both radiologists and pathologists. Cytogenetic and molecular genetic analyses provide complementary tools for differentiating soft tissue tumours. Our objective was to compare imaging criteria of malignancy with a new diagnostic gold standard, namely, pathological analysis combined with cytogenetic and molecular genetic analyses. Nineteen patients with a fatty tumour were included. All had computed tomography and/or magnetic resonance imaging examination before any biopsy or surgery. All had histopathological and cytogenetic and/or molecular genetic analyses. The imaging diagnosis of benign or malignant lesions was accurate in 15 cases, with 4 false positives for malignancy. Erroneous criteria were a large size (4 cases), and a mass that was not purely fatty. In conclusion, the main pitfall for a false positive radiological diagnosis of liposarcoma is certainly a large-sized tumour. Cytogenetic and molecular genetic analyses contribute to the diagnosis and can be performed at the same time with a core biopsy.