Well-differentiated liposarcoma/atypical lipomatous tumor can be difficult to differentiate from benign lipomatous tumors, especially on limited biopsy material. Adjunctive tests for MDM2 (murine double minute 2) have proven useful in whole-tissue sections; however, their utility has not been determined within the increasingly popular core needle biopsy. Herein, we compare the ability of MDM2 immunohistochemistry and MDM2 fluorescence in situ hybridization (FISH) to discriminate benign lipomatous tumors from well-differentiated liposarcoma on core needle biopsies. Well-differentiated liposarcoma (n=17) and an assortment of benign lipomatous tumors (n=37), which had concurrent or previous core needle biopsies, and resection specimens were subjected to both MDM2 immunohistochemistry and MDM2 FISH on both whole-tissue sections and corresponding core needle biopsy sections. Percentage tumor cells positive for MDM2 by immunohistochemistry and an MDM2:CEP12 FISH ratio was calculated in each biopsy and resection specimen pair and the results were compared. MDM2 FISH had a higher sensitivity (100%) and specificity (100%) compared with MDM2 immunohistochemistry (65 and 89%) in core needle biopsies, respectively. In addition, MDM2 immunohistochemistry had a false-positive rate of 11%, compared to 0% with FISH. The average MDM2:CEP12 ratio was similar in the biopsy material compared with the whole-tissue sections in both well-differentiated liposarcoma and the benign lipomatous tumor group of neoplasms. Detection of MDM2 amplification by FISH is a more sensitive and specific adjunctive test than MDM2 immunohistochemistry to differentiate well-differentiated liposarcoma from various benign lipomatous tumors, especially on limited tissue samples.