We examined the ability of a panel of allospecific (N = 9) and of TT-specific (N = 15) human inducer T-cell clones to respond to antigen presented by B cells or by monocytes. With one exception all T-cell clones responded equally well to antigen presented by monocytes, by lightly irradiated (1000 rads) peripheral blood resting B cells, or by heavily irradiated (7500 rads) Epstein-Barr virus (EBV)-transformed B cells. One alloreactive human T-cell clone, Clone A1, which recognized an HLA-DP-associated antigen proliferated in response to allogeneic monocytes and gamma-interferon-treated fibroblasts but not in response to allogeneic B cells even in the presence of autologous monocytes. Nonspecific conjugate formation between B cells and Clone A1 was normal. Yet in contrast to allogeneic monocytes, allogeneic B cells failed to induce a rise in the intracellular calcium ion concentration and failed to cause interleukin 2 (IL2) receptor expression in Clone A1. Neither interleukin 1 (IL1) nor phorbol myristate acetate (PMA) reversed the inability of Clone A1 to proliferate to allogeneic B cells. The failure of allogeneic B cells to stimulate A1 was not due to their lack of expression of the HLA-DP gene product recognized by Clone A1 or to excessive sialation of this product. These results suggest that Clone A1 recognizes an epitope associated with HLA-DP which is expressed on monocytes and on gamma-interferon-treated fibroblasts but which is either absent or altered on B cells.