BACKGROUND: External immunoscintigraphy using a single monoclonal antibody has been employed successfully to localize primary, recurrent, and occult colorectal carcinoma. This prospective study investigated the accuracy and sensitivity of external immunoscintigraphy when the combination or "cocktail" of radiolabeled monoclonal antibodies, CYT-103 (an IgG1a) and CYT-372 (an IgG2b) directed against TAG-72 and CEA, respectively, is given to patients with known or suspected colorectal cancer. METHODS: Eleven patients enrolled in this open label phase I/II study underwent preoperative external immunoscintigraphy after intravenous cocktail administration of two indium 111-labeled monoclonal antibodies (MoAb), CYT103 and CYT372. Antibody dose ranged from 0.2 mg (five patients) to 1.0 mg (six patients), each antibody radiolabeled with 2.5 mCi of indium 111, delivering a total dose of 5 mCi per patient. Planar and SPECT images were performed 2 to 5 days postinjection. Suspected lesions were surgically resected within 2 weeks of injection. RESULTS: A total of 23 lesions (sites) were identified in the eleven patients, 19 of which were confirmed by pathology (hematoxylin and eosin [H&E]). Cocktail immunoscintigrams identified 16 of the 19 confirmed lesions. Computed tomography (CT) scan detected 9 of the 19 lesions. The sensitivities of cocktail immunoscintigraphy and CT scan for the detection of colorectal cancer were 84% and 64%, respectively. The positive predictive value for immunoscintigraphy was 94%. The antibody scans detected six occult, previously unsuspected lesions. Cocktail immunoscintigraphy changed the surgical management in four of the 11 (36%) patients. CONCLUSIONS: The combination of In 111 CYT-103 and CYT-372 improved the sensitivity of external immunoscintigraphy for the detection of colorectal cancer compared to that obtained with a single MoAb imaging. Cocktail antibody imaging may enhance the staging and management of patients with cancers of colon and rectum.