Endostatin is a potent inhibitor of tumor angiogenesis. Interestingly, normative endostatin also exhibits an anti-tumor effect, which remains a mystery so far. Here, we show that intravenous injection of nonnative endostatin results in tumor inhibition effect. Soluble and active endostatin is isolated from human blood after the addition of normative endostatin in vitro. By fractionation of the whole blood, we surprisingly identify fibrinogen specifically binding to and inhibiting the aggregation of normative endostatin. Moreover, the anti-tumor activity of normative endostatin is substantially impaired in fibrinogen-deficient mice. Our studies demonstrate that fibrinogen facilitates the anti-tumor effect of normative endostatin, which also provides new insights into the novel physiological function of fibrinogen. (c) 2009 Elsevier Inc. All rights reserved.