Donor‐specific tolerance to heart allograft was induced in adult Lewis rats by pregraft donor‐specific blood transfusion (DST). We previously showed that this tolerant state is characterized by a dramatic inhibition of T cell and macrophage activation. In addition, tolerant animals could not mount an efficient anti‐donor humoral response whereas transfer of sera from rejecting animals triggered rejection in tolerant animals. This tolerance can be abrogated by daily post‐graft administration of recombinant IFN‐γ (rIFN‐γ). To elucidate the mechanisms of action of rIFN‐γ, T cell, macrophage and B cell functions were assessed in allograft recipients. IFN‐γ did not restore the expression of Th1‐related cytokine mRNA or the activated macrophage product inducible nitric oxide synthase in allografts. Importantly, rIFN‐γ treatment promptly restored the anti‐donor humoral response in DST‐treated recipients. We conclude that rIFN‐γ treatment in DST‐treated allograft recipients cannot reverse the unresponsive state of Th1 cells and macrophages infiltrating the graft, but can provide B cell help for IgG alloantibody production which is lacking in these animals.