Introduction: Tumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of antiestrogen adjuvant therapy. We designed a pilot study to assess the feasibility and short-term efficacy of neoadjuvant letrozole and bevacizumab (anti-VEGF) in postmenopausal women with stage II and III estrogen receptor/progesterone receptor-positive breast cancer. Patients and Methods: Patients were treated with a neoadjuvant regimen of letrozole orally 2.5 mg/day and bevacizumab intravenously 15 mg/kg every 3 weeks for a total of 24 weeks before the surgical treatment of their breast cancer. Patients were followed for toxicity at 3-week intervals, and tumor assessment (a physical examination and ultrasound) was performed at 6-week intervals. Positron emission tomography (PET) scans were performed before therapy and 6 weeks after the initiation of therapy. Results: Twenty-five evaluable patients were treated. The regimen was well-tolerated, except in 2 patients who were taken off the study for difficulties controlling their hypertension. An objective clinical response occurred in 17 of 25 patients (68%), including 16% complete responses (CRs) and 52% partial responses. The 4 patients with clinical CRs manifested pathologic CRs in their breasts (16%), although 1 patient had residual tumor cells in her axillary nodes. Eight of 25 patients (32%) attained stage 0 or 1 status. The PET scan response at 6 weeks correlated with clinical CRs and breast pathologic CRs at 24 weeks (P <.0036). Conclusion: Combination neoadjuvant therapy with letrozole and bevacizumab was well-tolerated and resulted in impressive clinical and pathologic responses. The Translational Breast Cancer Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population.