Abstract CD30 ligand (CD30L), a member of the TNF family, is a type II membrane protein with a C-terminal extracellular domain that is homologous with the extracellular domains of other TNF family members. Also, like most TNF family members, the N-terminal cytoplasmic domain of CD30L is conserved across species, but not between family members, suggesting a possible biological function. Motivated by this observation, we investigated the potential for CD30L, when activated by cross-linking, to directly transduce a signal to the ligand-bearing cell. Cross-linking of CD30L by a mAb or by CD30-Fc fusion protein induced the production of IL-8 by freshly isolated neutrophils. Further, both cross-linking mechanisms produced a rapid oxidative burst. Indirect effects through CD30 were ruled out, since CD30L, but not CD30, is expressed on neutrophils. Expression of CD30L can be induced in peripheral blood T cells by cross-linking the CD3 component of the TCR. Peripheral blood T cells exposed to suboptimal concentrations of anti-CD3 increased metabolic activity, proliferated, and produced IL-6 in response to cross-linking of CD30L. These results indicate that cross-linked CD30L can transduce a signal to the ligand-bearing cell. This "reverse signaling" via CD30L taken together with previously published data concerning other ligands in the TNF family strongly suggest that, as a rule, TNF family members and their cognate receptors signal bidirectionally, blurring the distinction between ligand and receptor.