PGE represent oxygenation products of polyunsaturated essential fatty acids and are important regulators of cell-mediated immune responses. Because oils enriched in such fatty acids reduce inflammation and tissue injury in vivo, we examined the effects of these PGE precursors on IL-2-driven growth of human T lymphocytes. Dihomogamma linoleic acid (DGLA), AA, and their metabolites (PGE1 and PGE2, respectively) strongly inhibited short- and long-term growth of IL-2-dependent T cell cultures; EPA was much less inhibitory and its product, PGE3, failed to suppress IL-2 responses. Short-term pretreatment of the cells with DGLA or AA and removal of the fatty acids before the proliferation assay resulted in a smaller reduction in [3H]TdR incorporation. PGE and fatty acids did not alter the number of high affinity IL-2 binding sites on the T cell cultures but reduced the percentage of cells expressing CD25 and HLA class II molecules. No PGE was detected in supernatants from the fatty acid-treated cultures. Moreover, indomethacin, a cyclooxygenase inhibitor, did not reverse the antiproliferative effects of the fatty acids. Together, these findings indicate that fatty acids can inhibit IL-2-driven T cell growth via a PGE-independent mechanism and might be relevant to inflammatory diseases associated with persistent T cell activation.