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In a series of 84 head and neck patients, a statistically significant correlation was observed between high serum soluble interleukin (IL)-2 receptor alpha (sIL-2Rα) ( P = 0·034) and metalloproteinase-9 (MMP-9) concentrations ( P = 0·036) at diagnosis and a shorter survival of these patients. As MMP-9 has been shown to mediate cleavage of IL-2Rα (CD25) by preactivated T cells, we looked for a relationship between MMP-9 expression and soluble IL-2Rα serum concentrations in these cancer patients. We did not find any correlation between intratumoral expression of MMP-9 or serum MMP-9 concentrations and serum sIL-2Rα levels. These results led us to reassess the role of MMP-9 in the release of sIL-2Rα. Treatment of Kit225 leukaemic cells with recombinant MMP-9 slightly decreased membrane CD25 expression and was associated with an increased concentration of sIL-2Rα in the supernatants. However, using a selective inhibitor of MMP-9 we did not succeed in specifically inhibiting the release of sIL-2Rα by the Kit225 cell line or by phytohaemagglutinin (PHA)-activated peripheral blood mononuclear cells. In addition, in a preclinical mouse model, basal serum sIL-2Rα concentrations and sIL-2Rα production by activated cells were not altered in MMP-9-deficient mice compared to wild-type mice. Interestingly, a broad spectrum metalloproteinase inhibitor inhibited the release of sIL-2Rα by PHA-activated peripheral blood mononuclear cells, suggesting that in contrast with current views concerning the major role of MMP-9 in the cleavage of membrane IL-2Rα, other proteases are involved in the shedding of sIL-2Rα. MMP-9 and sIL-2Rα appear therefore as independent prognostic markers in head and neck cancers. [ABSTRACT FROM AUTHOR]