Antagonism of the CD154/CD40 pathway is a highly effective means of inducing long-term graft survival in preclinical models. Using a fully allogeneic murine transplant model, we found that CD154 blockade was more effective in prolonging graft survival than was CD40 blockade, raising the possibility that CD154 binds a second receptor. To test this, we queried the impact of CD154 antagonism in the absence of CD40. Data indicated that anti-CD154 functioned to reduce graft-infiltrating CD8 T cells in both WT and CD40 hosts. Because it has recently been reported that CD154 can ligate CD11b, we addressed the impact of blocking CD154-CD11b interactions during transplantation. We utilized a specific peptide antagonist that prevents CD154 binding of CD11b but has no effect on CD154-CD40 interactions. CD154:CD11b antagonism significantly increased the efficacy of anti-CD40 in prolonging allograft survival as compared to anti-CD40 plus control peptide. Mechanistically, CD154:CD11b antagonism functioned to reduce the frequency of graft-infiltrating CD8 T cells and innate immune cells. These data therefore demonstrate that blocking CD154 interactions with both CD40 and CD11b is required for optimal inhibition of alloimmunity and provide an explanation for why CD40 blockers may be less efficacious than anti-CD154 reagents for the inhibition of allograft rejection.