We have examined the application of 90Y-DOTA-cPAM4, anti-MUC1 IgG, in combination with the front-line drug gemcitabine as a potential therapeutic for pancreatic cancer. Athymic nude mice bearing CaPan1 human pancreatic cancer xenografts were administered 2 mg of gemcitabine on days 0, 3, 6, 9 and 12 with concurrent 90Y-DOTA-cPAM4 (100 μCi) provided on day 0. A second group of mice received a second cycle of treatment 5 weeks after the start of the first cycle. Control groups of mice included those that received either treatment arm alone, the combined modality treatment employing a nontargeting control antibody (hLL2, anti-B-cell lymphoma) and a final group that was left untreated. Gemcitabine administered as a single agent provided no antitumor effect. A single cycle of the combined 90Y-DOTA-cPAM4 and gemcitabine treatment provided greater inhibition of tumor growth than was observed for any of the other treatment procedures. Tumor growth was delayed for a period of 7 weeks. Two cycles of gemcitabine with concomitant 90Y-DOTA-cPAM4 yielded significant tumor regression and increased median survival to 21 weeks vs. 12 weeks for mice receiving a single cycle of therapy (p<0.024). Median tumor volume doubling-times were 18 weeks in mice treated with 2-cycles of therapy vs. 7 weeks in mice given only 1-cycle (p<0.001), and 3.5 weeks for the group that received 2-cycles of gemcitabine concomitant with equitoxic nontargeting 90Y-DOTA-hLL2 (p<0.001). These data suggest that addition of 90Y-DOTA-cPAM4 RAIT to a gemcitabine treatment regimen may provide enhanced antitumor efficacy for the treatment of pancreatic cancer. © 2004 Wiley-Liss, Inc.