The synthesis of prostaglandin, prostacyclin, and thromboxane, which requires the enzyme prostaglandin H (PGH) synthase (cyclooxygenase), is a general property of histiocytes, monocytes, and Langerhans cells. Previously the authors reported the production of prostaglandin E2 in a Hodgkin's cell line, KM-H2, and suggested that these cells therefore have a functional similarity to histiocyte-related cells. The present study confirms that the Hodgkin's neoplastic (Reed-Sternberg, H-RS) cells in tissue are also capable of producing prostaglandins by demonstrating the presence of PGH synthase in these cells in B5-fixed, paraffin-embedded tissue sections. It was found that the H-RS cells from seven of ten patients with Hodgkin's disease were stained variously with anti-PGH synthase antibodies. In normal and reactive lymphoid tissues, anti-PGH synthase staining was restricted to histiocytes, endothelial cells, and interdigitating reticulum cells. Thus, this study provides further evidence for a possible relationship between H-RS cells and histiocytes or interdigitating reticulum cells; this relationship has also been supported by information obtained in extensive immunologic, biochemical, and cell-differentiation studies. The secretion of PGH-synthase products, especially prostaglandin E2, in H-RS cells may play a major role in the regulation of cellular immunity in patients with Hodgkin's disease.