The immunomodulatory role of anti-idiotypic antibodies (Ab2) in patients with gastrointestinal cancer has been demonstrated in two types of clinical trials. In the first, cancer patients were treated with a monoclonal antibody (MAb) defining a tumor-associated antigen (Ag). MAb administration initiated an idiotypic network as demonstrated by the induction of both Ab2 and anti-anti-idiotypic antibodies (Ab3) in the treated patients. The Ab3 bound to tumor cells and isolated tumor Ag with the same specificity as the Mab (Ab1) at the beginning of the idiotypic cascade. A beneficial role of Ab3 is postulated for patients showing delayed clinical responses to MAb therapy. In a recent trial, patients with advanced colorectal cancer responded to immunization with Ab2 that functionally mimicked in vitro and in vivo (animals) a gastrointestinal tumor-associated Ag by developing highly specific Ab3 with anti-tumor binding reactivities. Thus, Ab2 are promising agents in immunotherapy approaches to cancer. These studies suggest an immunoregulatory role for Ab2 in cancer patients. Modulation of cellular immune responses by Ab2 in cancer patients will be an important consideration in future studies.