Anti-angiogenesis therapy is one of the most promising strategies for the treatment of cancer. We investigated the anti-angiogenesis activity of an extract from the ark shell Scapharca subcrenata and attempted to purify the active compounds. The crude extract of the ark shell inhibited the proliferation of human vein endothelial cells (HUVEC-1) and tube formation by human dermal microvascular endothelial cells (HMEC-1). The methanol extract of the viscera of the ark shell showed activity. The ark shell extract acts as an angiogenesis inhibitor and could be developed further as a health substance, functional food, and anticancer agent.