The immune response of 23 rhesus monkeys against different murine monoclonal antibodies (mAb) administered in vivo as immunosuppressive agents has been analyzed. Seven mAb specific for either helper-inducer (CD4 molecules) or cytotoxic/suppressor (CD8 molecules) T cells, that cross-react with monkey lymphocytes, were administered i.v. for 10 consecutive days in rhesus monkeys. Nineteen of the animals were recipients of a skin or renal allotransplant. Nineteen out of the 23 monkeys developed a significant immune response against the injected monoclonal. This response was restricted in its specificity since unrelated murine monoclonals were not recognized by the monkeys' anti-monoclonal immunoglobulins. Fine analysis of the monkeys' sera revealed that the antibodies produced against the xenogeneic proteins selectively exhibited two major specificities i.e., anti-isotypic and anti-idiotypic. On a practical basis, these results suggest that an animal already immunized against a given mAb should still be sensitive to the therapeutic effect of another monoclonal sharing the same specificity but different idiotype.