The surgical removal of primary tumours has been associated with the subsequent growth of previously dormant metastases. This accelerated growth has previously been ascribed to the removal of the primary tumour and the anti-angiogenic factors they produce, such as angiostatin and endostatin. Endotoxin or lipopolysaccharide (LPS) is a cell wall constituent of gram negative bacteria, ubiquitously present in air and endogenous gut bacteria, that may be introduced during surgery. LPS has been shown to be angiogenic and vascular endothelial growth factor (VEGF) is the most potent angiogenic cytokine identified to date. The role of endotoxin in surgically induced metastatic tumour growth, the therapeutic use of anti-endotoxin agents in the perioperative period, the regulation of VEGF expression by endotoxin and the effect of VEGF and endotoxin on tumour cell survival was examined. A murine model of experimental metastasis was established where no primary tumour was present. This allowed the effect of the surgical procedure on metastatic growth to be examined in the absence of any possible angiostatin / endostatin effect. Animals undergoing open surgery or laparoscopy with air sufflation of the peritoneum displayed increased metastatic tumour burden, reflected in higher proliferation and lower apoptosis within the metastases. Circulating levels of VEGF were also elevated in these groups and correlated with plasma levels of endotoxin. These changes were not observed in a group receiving laparoscopy with sterile C 0 2. Endotoxin injection resulted in similar effects, with increased metastatic burden and significantly higher serum VEGF levels than controls. The anti-endotoxin agent, rBPI21, reduced metastatic growth and serum VEGF levels in mice following LPS injection or open surgery, whereas the monoclonal antibody, E5, had no effect on tumour growth. LPS increased tumour cell proliferation and VEGF production. Endotoxin also increased proliferation, decreased apoptosis and enhanced the production of VEGF by endothelial cells and resulted in increased angiogenesis in vivo. LPS, through the induction of VEGF, or VEGF alone increased Bcl-2 expression in tumour cells resulting in a significant decrease in tumour cell apoptosis. These results demonstrate that endotoxin plays a role in the enhanced growth of metastases following surgical trauma by altering the critical balances governing tumour growth. Treatment with the antiendotoxin agent, rBPI2), blocked post-operative growth of metastases. Endotoxin regulates immune and tumour cell production of VEGF. Furthermore, endotoxin, through the induction of VEGF, or VEGF alone act as survival factors for tumour cells.