The interstitial fluid of MTW9A and Walker carcinomas and their ethanol extract induced strong angiogenic response in the rabbit (New Zealand White) corneal test. The fluid collected in vivo was rich in E-type prostaglandins, and prostaglandin E1 (PGE1) in particular was strongly angiogenic at the lowest dose as compared with the angiogenic responses of prostaglandins E2, I2, and F2 alpha. Neoplastic fibroblasts also induced a strong angiogenic response, but in indomethacin-treated rabbits neovascularization failed to occur. Copper was concentrated in the cornea during PGE1-induced neovascularization, and copper-deficient rabbits were unable to mount an angiogenic response in the corneal test. Ceruloplasmin, the copper carrier of plasma, was found to be angiogenic at high doses. In indomethacin-treated rabbits, however, ceruloplasmin at the same high doses failed to induce angiogenesis. The experiments are interpreted to indicate that angiogenesis is the end result of a sequence of events, two of which are PGE1 production and copper mobilization in the tissue where neovascularization occurs.