Twenty-two spindle cell lipomas and seven pleomorphic lipomas were investigated immunohistochemically in order to study the differentiation of the non-adipocytic elements. In all cases, neither spindle cells nor pleomorphic cells reacted with antibodies to a monocyte/macrophage antigen (MAC-387), fibronectin, laminin or type IV collagen. The absence of demonstrable basement membrane material argues against the possible prelipoblastic nature of these cells. With the antibody to S-100 protein, spindle cells were immunonegative, whereas pleomorphic cells sometimes revealed an intracytoplasmic weak to moderate staining reaction. In the light of what is known about the development of adipose tissue, our results would support the hypothesis of Bolen and Thorning (Am J Surg Pathol 1981; 5: 435-441) that spindle cell lipoma is composed of adipocytes and non-fat storing immature mesenchymal cells. It would appear that pleomorphic lipoma is similarly derived but that in some cases adipocytic differentiation is also abnormal. The characteristic clinical distribution of these two types of tumour may be of relevance in determining the cause of these unusual benign patterns of differentiation.