Carcinoembryonic antigen (CEA) is an attractive target molecule of radioimmunotherapy (RIT). To enhance RIT's therapeutic efficacy, the fractionation of radiolabeled antibody doses is an attractive strategy. In this study, a fully human anti-CEA monoclonal antibody (mAb) C2-45 was selected by virtue of its lack of immunogenicity, and the effectiveness of fractionated RIT with yttrium-90 (⁹⁰Y)-labeled mAb C2-45 was evaluated. In LS180 tumor-bearing mice, indium-111 (¹¹¹In)-labeled mAb C2-45 showed high and persistent tumor accumulation. Therapeutic studies were performed with single doses of ⁹⁰Y-mAb C2-45 (100 or 200 μCi) or double doses of 100 μCi ⁹⁰Y-mAb C2-45 at different intervals (5, 10, and 15 days). All ⁹⁰Y-mAb C2-45-treated mice showed inhibition of tumor progression, while the time to tumor progression was much longer in both the 200-μCi-treated group and the double 100-μCi-treated group than in the single 100-μCi-treated group. The therapeutic effect of the double 100 μCi administration at days 0 and 15 lasted significantly longer than that in the other treatment groups. These findings indicate that ⁹⁰Y-mAb C2-45 may be a promising agent for the treatment of CEA-positive cancer and that the fractionation of ⁹⁰Y-labeled antibody doses could enhance the therapeutic effect if performed according to an appropriate protocol.