Lipoprotein lipase (LPL) (EC 3.1.1.34) hydrolyzes triacylglycerols of very low density lipoproteins and chylomicrons. It is produced by several cell types, including macrophages, which are frequent in atherosclerotic lesions. The atherosclerotic plaque also contains activated T lymphocytes. We therefore investigated the possible regulatory effect of the T lymphocyte-derived lymphokine interferon-γ (IFN-γ) on macrophage LPL. Human monocyte-derived macrophages were treated with recombinant IFN-γ or conditioned medium from activated peripheral blood mononuclear cells for 3 days. LPL activity was thereafter measured in the culture medium and in cell homogenates. The enzyme protein was detected at a cellular level by immunocytochemistry and immunopredicipitation. Recombinant IFN-γ caused a profound decrease in macrophage LPL secretion. The IFN-γ-treated cells, however, still contained immunodetectable enzyme and the decrease in secretion was apparently only partly due to an inhibited synthesis. Conditioned medium from activated peripheral blood mononuclear cells also drastically decreased the macrophage LPL secretion. When the conditioned medium was treated with antibodies against IFN-γ, its down-regulating effect on macrophage LPL was totally removed. The data indicate that IFN-γ is inhibiting macrophage LPL at least in part via a reduction of LPL synthesis. A local release of IFN-γ may be important in the pathogenesis of atherosclerosis by affecting the lipid accumulation in the lesion.