Inflammatory liposarcoma is a variant of well-differentiated liposarcoma/atypical lipomatous tumor that consists of a mixture of lymphocytes, histiocytes, scattered atypical stromal cells, mature adipocytes, and rarely lipoblasts. When the inflammatory infiltrate predominates, the morphological features overlap with various fibroinflammatory disorders including sclerosing mesenteritis and retroperitoneal fibrosis, making the diagnosis difficult. Well-differentiated liposarcoma/atypical lipomatous tumor and dedifferentiated liposarcoma have characteristic molecular markers in the form of giant marker and ring chromosomes consisting of amplicons of 12q13-15, which includes MDM2. MDM2 immunohistochemistry (IHC) (Zymed; clone IF2) and dual color fluorescence in situ hybridization utilizing MDM2 (12q15) and chromosome 12 centromeric probes were performed on formalin-fixed and paraffin-embedded specimens from inflammatory well-differentiated liposarcoma (17 cases), sclerosing mesenteritis (14 cases), and idiopathic retroperitoneal fibrosis (10 cases). MDM2 expression as detected by IHC is a very sensitive tool in recognizing inflammatory well-differentiated liposarcoma (17 of 17); however, 21% (3 of 14) and 10% (1 of 10) of sclerosing mesenteritis and retroperitoneal fibrosis, respectively, displayed weak MDM2 immunoexpression. The MDM2 fluorescence in situ hybridization assay was very specific for inflammatory well-differentiated liposarcoma as 15 of 17 (88%) cases showed MDM2 amplification, whereas none of the cases of sclerosing mesenteritis or idiopathic retroperitoneal fibrosis showed amplification. Five cases of retroperitoneal fibrosis were noncontributory secondary to autofluorescence, potentially limiting the usefulness of the assay in certain situations such as inappropriate fixation. Increased MDM2 expression and/or MDM2 amplification can be employed to aid discrimination of inflammatory well-differentiated liposarcoma from fibroinflammatory mimics. MDM2 fluorescence in situ hybridization is a very specific method (100%), but less sensitive (88%), whereas MDM2 expression by IHC is very sensitive (100%), but less specific (83%). Therefore, a positive screen of difficult cases with MDM2 IHC would require confirmation by the fluorescence in situ hybridization. However, lack of MDM2 immunoexpression would rule out the possibility of inflammatory well-differentiated liposarcoma.