Our previous studies have shown that angiogenic factors protect endothelial cells from radiation-induced apoptotic death, and anti-angiogenics antagonized this effect and increased tumor response [14, 23]. Here we tested the effect of radiation therapy in combination with Pazopanib, a VEGFR inhibitor and a short-acting anti-angiogenic agent, on two mouse models of human sarcoma. Athymic or ICR/SCID mice were transplanted with JJ012 or MPNST3 sarcoma tumors respectively. When tumor volume reached 150 mm3 the tumors were treated with IR and/or Pazopanib, and their volumes were measured. As shown in Figure 1A and 1B, Pazopanib alone (single-dose or two-doses) administration resulted in a slight tumor growth delay relative to non-treated control mice in both sarcomas, whereas no significant difference between a single dose (−1 h) or two-doses (−8 h and −1 h) pre-administration cohorts was observed. SDRT (a single dose of 30 Gy) yielded a significant tumor response (p < 0.05 vs control) in MPNST3 tumors. Pre-treatment with single-dose or two-doses of Pazopanib prior to SDRT, radiosensitized MPNST3 response and led to enhanced tumor growth delay as compared to SDRT alone (Figure 1A). Notably, single-dose Pazopanib administration resulted in a greater tumor growth delay than in the two-doses Panzopanib administration cohort. A similar result was obtained in JJ012 tumors, SDRT alone (15 Gy) robustly reduced tumor growth, while pre-treatment with Pazopanib (single- or two-dose/s) significantly increased the radiation effect on tumor growth inhibition (Figure 1B, p < 0.05 vs SDRT alone). Although sarcoma tumors are modestly radio-responsive, pre-treatment with Pazopanib radiosensitized both JJ012 and MNPST3 sarcoma tumors and improved their response significantly.