TNF blockade modulates many aspects of the immune response and is commonly used in a wide array of immune-mediated inflammatory diseases. As anti-TNF induces anti-dsDNA IgM antibodies but not other antinuclear reactivities in human arthritis, we investigated here the effect of TNF blockade on the induction of TD humoral responses using cardiac allograft and xenograft models. A single injection of an anti-rat TNF antibody in LEW.1A recipients grafted with congenic LEW.1W hearts almost completely abrogated the induction of IgM and IgG alloantibodies. This was associated with decreased Ig deposition and leukocyte infiltration in the graft at Day 5. TNF blockade did not affect germinal-center formation in the spleen or expression of Th1/Th2 cytokines, costimulatory and regulatory molecules, and TLRs in spleen and graft of the recipient animals. Clinically, the abrogation of the induction of the alloantibodies was associated with a marked prolongation of graft survival. In contrast, anti-TNF did not alter acute xenograft rejection mediated by TI antibodies in a hamster-to-rat model. Taken together, these data indicate that TNF blockade abrogates the induction of TD humoral responses and accordingly, may have a beneficial effect in antibody-mediated inflammatory pathologies.