Abstract Insulin-like growth factor-binding protein 5 (IGFBP5) plays a role in cell growth, differentiation, and apoptosis. We found that IGFBP5 was markedly downregulated in ovarian cancer tissue, and that its overexpression in cancer cells induced cell death. In this study, we undertook to evaluate the functional significance of each region of IGFBP5 as a tumor suppressor of ovarian cancer. We found that the C-terminal region of IGFBP5 inhibited tumor growth in a 2774 cell xenograft mouse model, and that expression of VEGF, IL-6, and TNF-α were inhibited in 2774 cells stably expressing the C-terminus of IGFBP5. In order to evaluate its effects on tumor suppression, a peptide derived from the C-terminus of IGFBP5 (BP5-C) was synthesized. As a control, a peptide mutated in the IGF-binding site of BP5-C (BP5-Cmut), as well as peptides derived from the IGFBP2 C-terminus and heparin-binding site were also synthesized. Of these peptides, BP5-C and BP5-Cmut inhibited VEGF expression and NF-kB activity. Furthermore, BP5-C inhibited angiogenesis in an in vitro and an ex vivo system, consisting of HUVEC tube formation and rat aortic ring blood vessel sprouting, respectively. The in vivo effect of BP5-C on tumor growth was studied using i.p. injection of ovarian cancer 2774 cells into mice, as well as with a patient-derived xenograft mouse model. BP5-C peptide significantly inhibited tumor growth, angiogenesis, and VEGF expression in both xenograft models. These results suggest that the C-terminus of IGFBP5 exerts an anti-cancer activity by inhibiting angiogenesis via downregulation of VEGF in an IGF-independent manner, and may be considered as a novel angiogenesis inhibitor for the treatment of ovarian cancer. Citation Format: Jeong-Won Lee, Jae Ryoung Hwang, Young-Jae Cho, Yoo-Young Lee, Chel Hun Choi, Duk-Soo Bae, Byoung-Gie Kim. IGFBP5-derived peptide as a novel angiogenesis inhibitor for treatment of ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3384.