Desmoplastic stroma of colorectal adenocarcinomas contains a variety of extracellular matrix molecules, including hyaluronic acid (HA). Overexpression of the HA receptor CD44 and, in particular, its splicing variant CD44v6 has been described as a prognostic factor for patients with colorectal adenocarcinomas in some studies, but converse reports also exist. Our hypothesis is that these divergent results may be related to the fact that the function of CD44v6 depends on the HA content of cell-surrounding matrix. Therefore, we studied the expression of HA and CD44v6 in tissue samples of 145 patients suffering from colorectal adenocarcinomas using immunohistochemistry. Expression of HA was separately evaluated in tumor epithelium and stroma. We additionally examined the influence of HA on invasion and adhesion of colorectal adenocarcinoma cells in vitro. The results show that epithelial HA expression was not correlated with tumor stage but with lymph-node or distant metastasis. Patients with tumors expressing epithelial HA had a decreased overall survival ( P=0.017) as well as tumors with coexpression of epithelial HA and CD44v6 ( P=0.011). The latter issue remained an independent prognostic factor in multivariate analysis (relative risk 5.06; 95% confidence interval, 1.18-21.57; P=0.028). HA exclusively stimulated in vitro invasion of CD44v6-expressing cells. This stimulation was partly reversed by an anti-CD44v6 antibody. Our findings suggest that the adverse prognostic effect of CD44v6 in colorectal adenocarcinoma might be restricted to those tumors that have pericellular HA.