Abstract. Liposarcoma has previously been described in Western studies, however, such cases are rarely reported in the mediastinum. In addition, the presence of a liposarcoma with smooth muscle and neural differentiation has not been previously reported. Thus, the present study describes the rare case of a 28-year-old Chinese male admitted to our hospital with the symptoms of chest tightness and shortness of breath due to a recurrent fibrolipoma in the mediastinum. The resected tumor measured 23 cm at its largest diameter, with histopathological and immunohistochemical features indicating a well-differentiated liposarcoma accompanied by smooth muscle and neural differentiation. Following the resection, the patient underwent radiation treatment and remains alive with no evidence of disease recurrence at two months post-surgery. To the best of our knowledge, the present study is the first to report a case of liposarcoma with smooth muscle and neural differentiation, which indicates that liposarcomas could potentially originate from stem cells. The present study highlights the fact that pathologists must carefully investigate the histopathological characteristics of liposarcomas in order to obtain an accurate diagnosis.