Acute exposure of adult mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a selective suppression of proliferating cells of the immune system, including hematopoietic stem cells and B cells. Suppression of B cell-mediated or humoral immunity, in turn, results in altered host resistance to the parasite Plasmodium yoelii, a malaria model. Data presented in this study demonstrate a direct effect of TCDD on cultured lymphoctes resulting in a selective inhibition of the differentiation of B cells into antibody-secreting cells. A structure-activity study suggested that this inhibition was mediated by the Ah receptor. As previously defined by receptor binding studies in hepatic cytosol, active congeners were inhibitory, whereas inactive congeners were without effect. Using lymphocytes from congenic mice which differ only at the Ah locus, it was determined that the Ahbb-derived cells were inhibited by TCDD in vitro, whereas the Ahdd-derived cells were not. B cell differentiation thus provides a valuable model for understanding TCDD toxicity as well as the role of the Ah receptor in growth and differentiation.