Although it is already known that prostaglandins inhibit lymphocyte responses to mitogens the role of other products of arachidonic acid (AA) metabolism has not previously been investigated. Various inhibitors of AA metabolism were studied for their effects on mitogenesis in human lymphocytes, including imidazole, benzylimidazole, N-0164, L-8027, 5, 8, 11, 14 eicosatetraynoic acid, nordihydroguaiaretic acid, indomethacin, and aspirin. Selective or partially selective inhibitors of thromboxane synthesis, such as imidazole, benzylimidazole, N-0164, and L-8027 inhibited the mitogenic response at concentrations that also substantially affect thromboxane B2 synthesis in platelet-free lymphocyte preparations. Since indomethacin failed to reverse the inhibition by imidazole or N-0164, it is probably due to decreased thromboxane synthesis per se rather than secondary increases in prostaglandin synthesis. Eicosatetraynoic acid and nordihydroguaiaretic acid were more effective inhibitors of mitogenesis than of thromboxane synthesis. Since these agents also affect the lipoxygenase pathway, it is possible that part of their action is at this level. Thus, in addition to the inhibitory effects of prostaglandins on mitogenesis, other products of AA metabolism may promote the response.