The mechanisms underlying the impaired immune response frequently observed in cancer patients are poorly understood. Recently, a decreased expression of the signal-transducing CD3 zeta chains has been shown to occur in patients with colorectal or renal-cell carcinoma. Here, we have investigated the expression of the zeta molecule on lymphocytes from patients with advanced cancers including renal-cell carcinoma (n = 21), hepatic colorectal carcinoma metastases (n = 6), head-and-neck squamous-cell carcinoma (n = 7) or miscellaneous tumors (n = 7), using flow cytometry analysis of PBMCs with monoclonal antibody specific for the cytoplasmic domain of the zeta chain. The same analysis was also performed with patients undergoing IL-2 therapy (from 5 days up to 3 months i.v. or s.c.). PBMCs from patients (n = 41) showed a significant decrease in expression of the zeta chains as compared to the levels found in lymphocytes from healthy controls (n = 15), which was not reversed by IL-2 administration. Together, these results suggest that an alteration in the expression of the zeta-chain-transducing element in PBMCs may be a common cause of progressive immunosuppression in advanced cancer patients and that IL-2 is not sufficient to reverse this situation in vivo.