In recent years evidence has accumulated pointing out that graft rejection may be mediated not only by cellular but also humoral mechanisms. To study this problem in some detail, humoral responses were studied in mice subjected to skin grafting across the H-2 locus. B cell reactivity was measured during the first and second set reactions on consecutive days after transplantation until graft rejection. In vitro B cell activity was assessed by means of the reverse plaque-forming cell assay (PFC) using cells obtained from the lymph nodes and spleens. The results indicate that polyclonal activation of B cells is an integral part of the immune response to skin transplantation in mice. However, no correlation was found between the level of activation as demonstrated by the PFC and the time of graft rejection.