CD4(+) CD25(+) T-cells play a central role in initiating and maintaining anticancer immune response. On the other hand, CD25(+) is also expressed on tumor cells, the meaning of which is currently unclear. Therefore, this study was designed to determine the prognostic value of the presence of CD4(+) CD25(+) T-cells in squamous-cell carcinoma of the head and neck (SCCHN) and of CD25 on SCCHN tumor cells. Thirty-five (35) patients diagnosed with a primary untreated SCCHN were included in this study. Instantly snap-frozen resection or biopsy specimens were analyzed by immunohistochemistry. Histologic results obtained were related to overall, disease-free survival. On univariate analysis, both lymph-node status and the number of CD25(+) lymphocytes were associated with disease-free survival (p=0.039 and 0.04). On multivariate analysis, only the number of CD25(+) lymphocytes showed an association with disease-free survival (p=0.036), whereas both factors showed an independent association with overall survival (p=0.007 and 0.003). Contrarywise, the CD25 expression on SCCHN tumor cells was not associated with disease-free survival nor with overall survival. The presence of a high number of SCCHN-infiltrating CD4(+) CD25(+) lymphocytes is associated with a good prognosis in SCCHN patients. Contrarywise, the CD25 expression on SCCHN tumor cells is not associated with a prognosis in SCCHN patients, and its role and meaning remains to be elucidated.