The regulatory role of very low density lipoproteins (VLDL) in de novo protein synthesis and in natural killer (NK) mediated cytotoxicity against cancer cells was evaluated in IL-2 activated peripheral blood mononuclear cells (PBL). Supplementing of VLDL to the incubation medium induced a potent dose-related inhibitory effect on the synthesis and secretion of (35S) labelled proteins. The maximal inhibitory response was observed at 50 micrograms/ml cholesterol VLDL. The effect of VLDL on the IL-2 induced ability of lymphocytes to kill cancer cells and to interfere with target cell proliferation was then evaluated. Maximal cytotoxicity was observed at 50 micrograms VLDL/ml as cholesterol. This VLDL-dependent stimulatory effect was associated with a significant decrease in the proliferative effect of the medium conditioned by PBL. The possibility that VLDL mediate the regulation of immune functions by interacting with metabolic patterns expressed by IL-2 stimulated lymphocytes is discussed in light of these results.