Heparanase is an enzyme that degrades extracellular glycoprotein to release heparan sulfate molecules. CD44 variant exon 3 (CD44v3), a receptor for heparan sulfate, generates intracellular signals for cell migration. Production of CD44v3 and expression of heparanase were detected by immunohistochemistry and in situ hybridization, respectively. In 145 cases of colon cancer, heparanase mRNA and CD44v3 protein were detected in 46% and 43%, respectively. Co-expression of heparanase and CD44v3 was found in cases of 12% of Dukes' B, 32% of Dukes' C, and 57% of Dukes' D cases. Survival analysis found a significantly poorer prognosis in patients showing concurrent expression of heparanase and CD44v3 than in patients not showing both (p<0.0001). Concurrent expression of heparanase and CD44v3 might be a mechanism of cancer invasion and metastasis in colon cancer.