Experimental and clinical data indicated that perioperative administration of the hemostatic peptide desmopressin (DDAVP) can inhibit progression of residual metastatic cells. The compound seems to act by inducing an agonist effect on specific V2 vasopressin membrane receptors present in both tumor cells and endothelial cells. Here we explored the antitumor effects of DDAVP in cultured colon carcinoma cells and in a syngeneic Balb/c mouse model. Both human Colo-205 and mouse CT-26 colon carcinoma cell lines expressed the V2 receptor, as revealed by immunofluorescence. DDAVP (at doses ranging from 100 ng/ml to 1 μg/ml) exerted a modest but significant antiproliferative effect on cultured CT-26 and Colo-205 cells. In vivo, DDAVP (2 intravenous doses of 2 μg/kg) reduced accumulation of ascites and formation of intestinal tumor nodules in mice intraperitoneally inoculated with CT-26 cells. Perioperative administration of DDAVP significantly inhibited tumor progression in animals surgically implanted in the spleen with CT-26 cells, and caused some reduction in liver metastasis. Although DDAVP and 5-fluorouracil demonstrated additive cytostatic effects in vitro, no antitumor effects were observed in this study in mice receiving a single cycle of chemotherapy (25 mg/kg) in combination with the peptide. Our data suggest that DDAVP may be potentially used to minimize spread or survival of residual malignant cells during surgical procedures for colon and other gastrointestinal tumors.