Sarcomas of the posterior mediastinum are rare and correspond mostly to neurogenic tumors. We studied 18 cases of liposarcoma presenting in the posterior mediastinum; because of their unusual location, some of these tumors posed difficulties for diagnosis. There were 11 men and 7 women aged 29-87 years (mean: 57). The tumors were large lobulated masses ranging from 6 to 30 cm in greatest diameter (median: 15 cm). Symptoms included cough, dysphagia, and chest pain. Four patients were asymptomatic and the tumors were discovered incidentally on chest X-rays. Histologically, 10/18 (55%) cases were atypical lipomatous tumor/well-differentiated liposarcoma, one of which harbored a smooth muscle component (lipoleiomyosarcoma); 3/18 (16%) were de-differentiated liposarcoma, one of which also harbored a smooth muscle component; 3/18 (16%) were myxoid/round cell liposarcoma; and 2/18 (11%) were pleomorphic liposarcoma. The cases of well-differentiated liposarcoma were mostly of the sclerosing type; however, five of them also showed prominent myxoid stroma closely resembling myxoid liposarcoma. Immunohistochemistry was performed in selected cases; 4/8 cases tested showed focal positivity for S-100 protein and 5/8 cases showed nuclear positivity for MDM-2. The three cases of myxoid liposarcoma were all negative for MDM2. Both cases of lipoleiomyosarcoma showed positivity for SMA and desmin in the smooth muscle component. FISH was performed in two cases of well-differentiated liposarcoma and high levels of amplification of MDM2 at 12q13-15 were observed; the CHOP translocation at 12q13.1-q13.2 was absent in both cases. Complete surgical excision was performed in 11 cases; however, negative surgical margins were achieved only in four. Clinical follow-up ranging from 1 to 192 months (median 28 months) was available for 13 patients. Two patients with myxoid/round cell liposarcoma died of tumor after 4 months and 3 years, respectively. Both had widely disseminated metastatic disease at the time of death. Six patients (6/10) with well-differentiated liposarcoma were alive and well with no evidence of disease (at 4, 7, 12, 15, and 25 months) and three (3/10) were alive with disease (at 3, 4, and 6 months). One patient with well-differentiated liposarcoma had multiple recurrences and a liver metastasis after 14 years; however, the patient was alive and well at 16 years. Five patients were lost to follow-up. In general, the biologic behavior of liposarcomas in the posterior mediastinum seems to correlate well with the histologic subtype and mirrors that of their counterpart in the retroperitoneum.