The antiglobulin response is a major complication of mAb therapy. It has been suggested that, in clinical practice, this might be avoided by using human or chimeric mAbs, or by prior induction of tolerance to the therapeutic mAb. In this study, we show that it is possible to induce tolerance in mice to the constant regions of rat IgG2b mAbs by both classical deaggregation methods and by anti-L3T4 mAb therapy. Mice tolerant to IgG2b constant region determinants failed to make an antiglobulin response when immunized with a number of mAbs of the same isotype that had no binding specificity for mouse cells, but produced vigorous antiidiotypic responses to cell-binding mAbs. Binding of antibodies to hemopoietic cells rends their idiotypic determinants major immunogens even in the presence of tolerance to constant region epitopes. These findings suggest that the use of human or chimeric mAbs will not be sufficient to eliminate the antiglobulin response, and that additional methods need to be investigated.