In our institution, over 200 patients with gastro-intestinal tract carcinomas have been treated with monoclonal antibodies (MAbs) including CO 17-1A. In one clinical trial, MAbs were administered in combination with gamma interferon. Natural killer cell cytotoxicity (NK) and antibody-dependent cell-mediated cytotoxicity (ADCC) were studied in patients before treatment. Very low NK and ADCC activities were measured in metastatic cancer patients. NK cell lysis was enhanced during gamma-interferon treatment, associated with a modification of the Fc receptor expression, but no changes in the ADCC reactivities of leukocytes were noticed. Monoclonal antibodies were circulating for one to four weeks after a single dose infusion, independent of the patients' immune responses toward the administered MAb. Sixty-three percent of the patients mounted an anti-mouse immunoglobulin response. Anti-idiotypic antibodies were detected in 70% of the responding patients. Variations in the anti-mouse Ig responses were dependent on the therapeutic protocol. The immune responses were composed of IgM, IgA, and IgG (mainly IgG1, often associated with IgG2 and/or IgG3). In patients receiving MAbs together with gamma-interferon, development of the anti-mouse Ig responses were delayed with an increase in the anti-isotypic component and a decrease in the anti-idiotypic component as compared to patients treated with MAb alone. No correlation could be established with clinical results.