Fat necrosis of the breast is a relatively common reactive/reparative process that may be either primary, often after trauma, or secondary to prior surgery or therapeutic irradiation. Mammary fat necrosis may closely mimic breast neoplasia, both clinically and radiographically, and is thus frequently biopsied. In the majority of cases fat necrosis in the breast shows classic morphologic features and is a straightforward diagnosis. However, over the past several years we have seen a number of more challenging cases of mammary fat necrosis complicated by a distinctive cellular, spindled proliferation of macrophages, mimicking various spindle cell neoplasms of the breast. Herein we report our experience with such lesions. A total of 118 cases of fat necrosis involving the breast were retrieved from our institutional and consultation archives for the period 1994 to 2011. The final study group of 20 cases included only (1) consultation cases submitted specifically with concern for a spindle cell neoplasm and (2) institutional cases presenting as a mass lesion and showing an identical spindle cell proliferation. The tumors occurred in 20 women (mean age 58 y; range, 24 to 70 y), involved both breasts (left, 11 cases; right, 9 cases), and ranged in size from 0.8 to 2.5 cm (mean 1.5 cm). Additional clinical information was available for 18 (90%) patients; a history of ipsilateral breast carcinoma and prior therapeutic irradiation were documented in 7 of 18 (39%) and 6 of 18 (33%) patients, respectively. Radiographic reports and/or imaging was available for 17 (85%) patients; radiographic impressions were "suspicious for malignancy" (10 cases, 59%), "indeterminate" (2 cases, 12%), or "benign" (5 cases, 29%). The patients underwent core needle (14 cases, 70%) and excisional (6 cases, 30%) biopsies. The morphologic features of all cases were similar, showing a moderately cellular, fascicular proliferation of mitotically active, normochromatic, lightly eosinophilic spindled cells with mild nuclear variability, folded or grooved nuclei, and indistinct nucleoli. Chronic inflammatory cells and multinucleated giant cells were often admixed with the spindled cells, with more typical features of fat necrosis frequently present at the periphery. Immunohistochemical analysis performed at Mayo Clinic showed the lesional cells to express the histiocyte-associated markers CD163 (8 of 8, 100%), CD11c (8 of 8, 100%), and CD31 (4 of 8, 50%) and to be negative for keratins using the OSCAR monoclonal antibody (0 of 8, 0%). Studies conducted at outside institutions showed absent expression of various keratins, S100 protein, p63, and β-catenin protein. Histochemical staining for mycobacterial and fungal organisms was negative. Follow-up (18 patients, 1 to 120 mo, mean 37 mo) showed all patients to be alive without disease. Additional surgical procedures (6 patients) showed only fat necrosis. We believe that these lesions represent an exaggerated histiocytic reaction to fat necrosis in the breast. Awareness of this distinctive pseudotumor should help to prevent its misdiagnosis as various other mammary spindle cell neoplasms.