CD30 is a member of the tumor necrosis factor receptor superfamily, preferentially expressed by T cells producing type 2 helper (Th2) cytokines, whose ligand (CD30L) has been identified on B cells, activated macrophages, and a subset of activated T cells. We show here that cross-linking CD30 with an agonistic CD30-specific monoclonal antibody, as well as with CD30L(+) CD8(+) T cell clones or CD30L(+) B cells, enhanced HIV replication in CD4(+) T cells from HIV-infected individuals, and such a potentiating effect was inhibited by anti-CD30L antibody, The anti-CD30L antibody also exerted a suppressive effect on spontaneous HIV replication occurring in lymph node cells from an HIV-seropositive patient, showing CD30L expression by both B and CD8(+) T lymphocytes, Thus, CD30 triggering by CD30L-expressing cells may play an important role in the activation of HIV expression from latently infected CD4(+) T cells.