MAb-PAM4 is an anti-MUC1 antibody that has been shown to be reactive with 85% of pancreatic adenocarcinomas with no reactivity with normal pancreas or other tissues. Initial clinical studies have shown excellent targeting with high tumor/nontumor ratios. Gemcitabine, an analog of deoxycytidine, is currently a frontline treatment for pancreatic cancer. Acting via a number of metabolic pathways, gemcitabine is also a powerful radiosensitizer. Combined-modality, chemo/radiosensitization with gemcitabine and low dose 131I-PAM4 radioimmunotherapy was performed to determine if a more effective treatment procedure could be developed. Athymic nude mice bearing large (1 cm3) CaPan1 human pancreatic tumors were given a single treatment cycle consisting of gemcitabine, 333 mg/m2 administered on Days 0, 3, 6, 9 and 12 by intraperitoneal injection, along with either 100 or 200 μCi, 131I-PAM4 administered on Day 0 by intravenous injection. Gemcitabine did not interfere with the biodistribution of radiolabeled antibody. Specific tumor targeting was observed for 131I-PAM4, with a tumor/blood radiation dose ratio of 2.6 over the first 14 days. Gemcitabine alone and low dose radioimmunotherapy alone, each had no affect upon tumor growth; no statistical differences were noted in comparison to the untreated group. When combined, however, a statistically significant (p = 0.0324), synergistic anti-tumor effect was observed. Median survival time doubled for the combined treatment regimen compared to single modality treatment groups. The combined treatment modality was well tolerated by the mice. Our data show that combined gemcitabine with radioimmunotherapy may provide an improved alternative for the treatment of pancreatic cancer, achieving successful anti-tumor effects with low toxicity. © 2001 Wiley-Liss, Inc.