A variant form of CD44 that has additional amino acids in the common protein backbone (CD44-v6) seems to play a role in the metastasis of malignancies. We measured soluble CD44-v6 (sCD44-v6) by ELISA in 201 patients with malignant lymphoma. The sCD44-v6 level was significantly elevated in patients with non-Hodgkin's lymphoma (NHL) (n = 184). The sCD44-v6 level was correlated significantly with the standard sCD44 and soluble interleukin-2 receptor levels, but only weakly with serum lactate dehydrogenase (LDH). In 149 patients with aggressive NHL, the sCD44-v6 level was elevated in the subgroups with a high LDH level, stage III/IV disease, T-cell lymphoma, and high-intermediate or high risk group as identified by the International Prognostic Index (IPI). When the sCD44-v6 level was > or = 800 ng/ml the overall survival rate was significantly decreased (p = 0.0001). In the low + low-intermediate risk group (IPI) both overall survival rates (log-rank p = 0.0005, Wilcoxon p =0.002) were significantly decreased when the sCD44-v6 level was > or = 800 ng/ml. In multivariate analysis, sCD44-v6 was shown to be independent of the five prognostic factors in the IPI (age, performance status, number of extranodal sites, Ann Arbor stage and LDH level), so it may be useful for predicting the outcome of aggressive NHL.