Pancreatic cancer is characterized by an extremely poor prognosis. For the development of more effective immunotherapies, the systemic and local immunological escape mechanisms need to be further elaborated. These mechanisms may include the secretion of immunosuppressive cytokines, the local hindrance of tumor-infiltrating lymphocytes (TILs), or the loss of the signal transducing CD3 ζ-chain of TILs. In this study, we have analyzed these parameters in 116 patients suffering from pancreatic ductal adenocarcinoma. Mean concentrations of interleukin (IL)-10 and transforming growth factor-β1/2 were considerably higher than in control sera (P < 0.0001). Disseminated tumor cells were found in 16 of 39 cases. In 28 of 33 surgical specimens, TILs did not reach tumor cells in significant numbers, being “trapped” in the peritumoral tissues. We suggest this as a simple but highly effective tumor escape mechanism. In cases of a TIL/tumor cell contact, CD3 ζ was mostly lost. Overall, 27 of 33 surgical specimens, 9 of 19 peritumoral lymph nodes, and 13 of 25 peritoneal lavage specimens showed significant loss of CD3 ζ (P < 0.02). Elevated concentrations of IL-10/TGF-β1/2 were, in all but one of three cases, correlated with a CD3 ζ loss in corresponding specimens. Patients with disseminated tumor cells also showed a CD3 ζ loss in all but two corresponding tumor specimens. These results present strong evidence for an active systemic immunosuppression in pancreatic cancer, as shown by elevated IL-10 and TGF-β1/2 serum levels as well as the presence of disseminated tumor cells. Killing of tumor cells by potentially cytotoxic TILs is obviously suppressed by the prevention of a direct TIL/tumor cell contact and the inactivation of TILs, as shown by a severe loss of CD3 ζ. In addition to active immunization strategies, successful immunotherapies have to focus on restoring in vivo T-cell function to improve the almost always fatal prognosis of pancreatic cancer.