We have previously demonstrated that external beam irradiation can increase radiolabeled monoclonal antibody (MAb) targeting of tumors expressing carcinoembryonic antigen (CEA), a secreted glycoprotein. Increased tumor uptake was seen with both protons and gamma radiation (60Co). However, although pre-irradiation with protons resulted in greater activity within tumors than conventional radiation, normal tissues also exhibited increased uptake. This suggested that proton beam irradiation allowed more CEA to escape and bind to radiolabeled MAb in sites other than tumor. The purpose of the present study was to determine if a similar effect could be achieved, but without an increase in normal tissue activity, with a MAb directed against a cell-bound antigen. T380 and LS174T human colon tumors were implanted s.c. into athymic nude mice and irradiated with 10 Gy 60Co or proton beam. 111In-CYT-103 MAb (anti-TAG-72) was injected i.p. 2 hr later and the biodistribution of activity was determined 2 days thereafter. Tumor size at the time of external beam irradiation and biodistribution studies was similar among the groups within each tumor type. Increased targeting of radiolabeled MAb within tumors was not observed in either model after external beam irradiation compared to their respective nonirradiated controls, although some differences were observed in normal tissue uptake. These findings demonstrate that preirradiation for the purpose of enhancing MAb delivery to the tumor site is not a universal phenomenon and may be successful only with certain antibody/tumor antigen systems.