The effect of marine n-3 polyunsaturated fatty acids on proliferation of human T-cells in vitro was compared to other polyunsaturated, monounsaturated and saturated fatty acids. Monoenes and saturated fatty acids had little effect on T-cell proliferation. Eicosapentaenoic acid and docosahexaenoic acid exerted a strong dose-dependent inhibitory effect on proliferation of mitogen- or antigen-stimulated T-cells, similar to that observed for arachidonic acid. Sixty microM of albumin-bound eicosapentaenoic acid or arachidonic acid promoted 25-40% inhibition of proliferation of T-cells stimulated with mitogen, whereas the same concentration of albumin-bound docosahexaenoic acid promoted 60% inhibition. When epidermal cells (Langerhans cells) were used as antigen-presenting cells, 100 microM of albumin-bound eicosapentaenoic acid or arachidonic acid caused 40% inhibition on T-cell proliferation. Low density lipoprotein (LDL), isolated after four months of dietary intake of fish oil or corn oil, inhibited mitogen-stimulated T-cell proliferation in a dose-dependent manner. Fish oil- and corn oil-enriched LDL showed similar ability to inhibit T-cell proliferation. Epidermal cells preincubated with docosahexaenoic acid, and extensively washed before adding purified T-cells and antigen, resulted in a strong inhibition of T-cell proliferation, whereas preincubation of purified T-cells with docosahexaenoic acid did not cause any inhibitory effect. Cyclooxygenase and lipoxygenase inhibitors (indomethacin, acetylsalicylic acid, nordihydroguaertic acid) did not affect the antiproliferative effect of eicosapentaenoic acid and arachidonic acid, neither did the antioxidants butylated hydroxytoluene or alpha-tocopherol. Eicosanoids, (PGE2, PGE3, LTB4, LTB5 and lipoxin A or lipoxin B) added directly to mitogen-stimulated peripheral blood mononuclear cells (PBMC) did not influence T-cell proliferation significantly. Decreased viability was observed when mitogen-stimulated lymphocytes were cultured with essential polyunsaturated fatty acids, whereas the viability of unstimulated lymphocytes was hardly influenced by the same fatty acids. We conclude that; (a) pharmacological albumin-bound concentrations of the highly unsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid promote a strong antiproliferative effect on mitogen- and antigen-stimulated human T-cells: (b) docosahexaenoic acid can suppress accessory cell function and consequently suppress T-cell activation; (c) physiologic concentration of LDL particles rich in n-3 and n-6 fatty acids, both promote a dose-dependent antiproliferative effect on mitogen-stimulated PBMC; (d) the inhibition is independent of eicosanoid metabolites; and (e) lipid peroxidation seems unlikely to be responsible for the antiproliferative effect.