The overexpression of vascular endothelial growth factor (VEGF) in varying types of solid tumor renders radioimmunotherapy (RIT) with the anti-VEGF antibody bevacizumab (BV) a promising treatment. However, the slow blood clearance of BV, which may increase the occurrence risk of hematotoxicity, hinders the application of BV-RIT. Using the avidin chase is a long-known blood clearance enhancement strategy for biotinylated-mAb. To enhance RIT efficacy by increasing the radioactivity dose, we evaluated the ability of avidin to accelerate the blood clearance of yttrium-90 (90Y)-labeled biotinylated BV (90Y-Bt-BV) in a xenograft mouse model of triple-negative breast cancer (TNBC). The biodistribution study in the TNBC xenograft mice confirmed the high and specific tumor accumulation of the indium-111 (111In)-BV. The blood clearance enhancement effect of the avidin chase was demonstrated in the normal mouse studies with 111In-Bt-BV. In the subsequent biodistribution studies with the tumor-bearing mice, an optimized dose of avidin injection subsequent to 111In-Bt-BV with an appropriate biotin valency successfully accelerated the blood clearance of 111In-Bt-BV without impairing its tumor accumulation level. The avidin chase enabled an increase in the maximum tolerated dose of 90Y-Bt-BV to twice as much as that of 90Y-BV in tumor-bearing mice and thereby significantly improved the therapeutic effect of 90Y-Bt-BV compared to 90Y-BV (p &lt
0.05). These results underscored the potential usefulness of 90Y-bevacizumab-RIT with the avidin chase for the treatment of VEGF-positive tumors.