An antimouse immune response is invariable following administration of murine monoclonal antibody (mAb), precluding effective multidose therapy. In advanced colorectal cancer patients, we carried out a pilot study with multiple doses of 131I-labeled CC49 administered with deoxyspergualin (DSG), an immunomodulator, to determine its effect on immune response. Cumulative toxicity and efficacy were also evaluated. Six patients with tumor-associated glycoprotein 72-expressing colorectal cancer were treated i.v. with 15 mCi/m2 131I-labeled to 20 mg mAb CC49 biweekly, along with concurrent DSG 200 mg/m2 daily for 5 days, for a maximum of four courses. None had received prior murine mAbs. All patients had targeting of radioactivity to known tumor sites following initial infusion. Four of six patients received all four courses of therapy, three without any acute side effects. In these patients, there was no change in serum clearance with variable tumor targeting following repeat infusions. Two patients had = grade II anaphylactoid reactions, which were treated without sequelae. One of these had faster serum clearance of radioactivity following repeat infusions of 131I-labeled CC49. Human antimouse antibody titers in all patients were significantly less compared to concurrent times in patients receiving CC49 without DSG (P < 0.05). There was no correlation between the human antimouse antibody titer and serum clearance or tumor targeting of 131I-labeled CC49. There were no clinical responses. We concluded that multiple doses of murine antibody 131I-labeled CC49 can be safely administered with no change in serum or whole-body kinetics in 50% of patients treated biweekly. DSG may reduce the human immune response to the murine mAb.