In this paper we have examined the cooperation between TNF and PAF in the generation of superoxide anion (O2-) in vitro by polymorphonuclear cells (PMNs), as well as their ability to induce joint inflammation when injected into the knee of healthy rabbits. TNF and PAF directly stimulated the generation of a small amount of O2- by PMNs. TNF pretreatment of PMNs induced a certain synergy in the O2- production, when these cells were later stimulated with PAF. When PAF receptor antagonists were added, the O2- release was inhibited. The injection of either TNF or PAF into the knee joint of normal rabbits induced a dose-dependent accumulation of leukocytes in the synovial cavity 24 h after administration. When TNF was administered 1 h before PAF, a synergistic response in the accumulation of leukocytes in the joint fluid was noted. The administration of BN 52726 by the intraperitoneal route markedly inhibited the cell accumulation induced by TNF and PAF. Histological signs of inflammation were noted in the synovial lining of joints injected with TNF and PAF. These results suggest that TNF can amplify the inflammatory response induced by PAF. PAF antagonists can inhibit this effect and thus may be of therapeutic value in different pathological situations.