Purpose: The purpose of this study was to determine the feasibility and maximum tolerated dose of9OYttrium-CC49 (90Y-CC49) as the radioimmunotherapy (RIT) component of an i.p. combined modality treatment for recurrent ovarian cancer. Experimental Design: A Phase I trial of90Y-CC49 RIT was conducted in ovarian cancer patients who had persistent or recurrent intra-abdominal disease, had failed one or two prior chemotherapy regimens, and demonstrated TAG-72 expression. Patients were treated with a previously established combined modality treatment protocol of s.c. IFN α2b, i.p. paclitaxel, and increasing dosages of i.p.90Y-CC49. Patients were monitored for toxicity, generation of human antimouse antibody response, and clinical efficacy. Results: Twenty eligible patients were treated per study specifications. All patients had been treated with debulking and paclitaxel/carboplatin-based chemotherapy at initial diagnosis. The patients included 11 patients with persistent disease at the time of second look laparotomy and 9 patients with delayed recurrence. Patients were treated with i.p.90Y-CC49 given in combination with s.c. IFN α2b (dose of 3 x 106 units for a total of four doses) and i.p. paclitaxel (dose of 100 mg/m2). RIT treatment was associated with primarily hematological toxicity. The maximum tolerated dose of i.p.90Y-CC49 was established at 24.2 mCi/m2 in this combined regimen. Of nine patients with measurable disease, two had partial responses lasting 2 and 4 months. Of 11 patients with nonmeasurable disease, median time to progression was 6 months in 7 patients who recurred; 4 of these patients remain no evidence of disease at 9+, 18+, 19+, and 23+ months. Conclusions:90Yttrium-CC49-based RIT in combination with IFN α2b and i.p. paclitaxel is feasible and well tolerated at a dose of ≤24.2 mCi/m2.