We have previously shown that anti-idiotypic antibodies (Ab2) that functionally mimic the epitope defined by anti-colorectal carcinoma (CRC) monoclonal antibody (Ab1) CO17-1A induce in cancer patients highly specific anti-anti-idiotypic antibodies (Ab3) which are Ab1-like in their binding specificity to tumor cells and antigen. Ab1 GA733, originally produced against gastric carcinoma, binds to the same antigen as Ab1 CO17-1A, but to a different epitope. Ab2 against Ab1 GA733 produced in goats have been previously shown in experimental animals to functionally mimic the epitope defined by the Ab1. For the purposes of studying immune responses, this Ab2 preparation was administered to 12 patients who had previously been diagnosed with CRC but whose tumors were excised prior to Ab2 therapy. Patients were injected subcutaneously with escalating doses (0.5-4 mg) of Ab2 precipitated to alum. Ten of the 12 patients produced antibodies to the administered Ab2. In six patients a fraction of these antibodies bound specifically to the Ab2 and not to normal goat IgG. These anti-anti-idiotypic antibodies (Ab3) shared idiotopes with the Ab1 and bound to antigen-positive, but not antigen-negative, cultured tumor cells. The Ab3 specifically inhibited binding of the Ab1 to tumor cells and therefore may bind to the same epitope as Ab1. Our studies demonstrate that Ab2 are highly specific modulators of cancer patients immune responses to their tumors.