Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is known to inhibit a variety of immune functions. However, the mechanisms of action of THC-induced immunosuppression are unclear. Because THC is known to affect arachidonic acid metabolism in non-lymphoid cells and because arachidonic acid metabolites are important regulators of the immune response, a detailed examination of the effects of THC on arachidonic acid metabolism in human peripheral blood mononuclear cells (PBMC) was performed. THC increased the amount of label released from PBMC prelabeled with [3H]-arachidonic acid. Further studies were performed using RP-HPLC to determine whether the increase in label release from cell membranes was due to the release of free [3H]-arachidonic acid or metabolites. Our results indicated that THC increases the production of the eicosanoid 12-HETE from PBMC. To determine whether other metabolites, such as the leukotrienes, were also affected by THC, leukotriene B4 (LTB4) was measured by enzyme immunoassay. THC was shown to increase markedly the production of LTB4 from PBMC stimulated with the calcium ionophore A23187. These results indicate that THC alters arachidonic acid metabolism in lymphocytes by increasing the production of lipoxygenase products.