Although two-thirds of colorectal cancer patients are cured by surgery, approximately 50% of the patients with this disease develop locally recurrent or distant metastases during the course of their illness. The aim of this study was to identify metastatic sites associated with poor prognosis in rectal cancer and then to investigate methods that can prevent the development and growth of metastases and optimise uptake of drugs at these sites in animal models. In a defined population, 151 patients with irresectable metastatic or local rectal cancer were identified. Bilateral liver involvement, abnormal liver function tests, paritoneal growth or abdominal lymph node metastases implied a poor prognosis. In a study on Wistar rats with liver metastases from colorectal cancer, blocking of hyaluronan uptake and elimination by the liver enhanced the hyaluronan uptake in liver metastases. Hyaluronan may thus be used to promote uptake of drugs in specific hyaluronan receptor-positive turnout sites. Adjuvant intravenous radioimmunotherapy delivered as a specific or unspecific monoclonal antibody prevented human colonic cancer calls inoculated into the portal vein of nude rats from developing into liver metastases. Furthermore, intraperitoneally administered radioimmunotherapy inhibited the growth of peritoneal metastases. Blocking of 5-FU absorption with a vasoconstrictive agent enhanced the uptake of 5-FU in peritoneal metastases. In addition, the uptake of 5-FU in peritoneal metastases could be improved when these turnouts were mechanically disintegrated by surgical turnout reduction and the drug was given intraperitoneally.