The mechanisms of correcting immune disorders in patients with pancreatic cancer requiring major surgery procedures by introducing perioperative immune-enhancing diet (immunonutrition) are still unclear. The purpose of our study was to investigate the effect of pancreatic cancer, extensive surgery and immunonutrition versus enteral standard nutrition on the apoptotic signaling pathways. The randomized studies were performed in 72 patients before and after pancreatic cancer resection with preoperative standard (Group I) or enteral immunonutrition (Group II). The expressions of Bcl-2, Bax, caspases-3, -9, NF-κB, PARP-1/89 kDa, TNFR1/CD120a and Fas/CD95 in peripheral blood lymphocytes were assessed by western blot analysis and flow cytometry before and on day 1, 3 and 7 after surgery. In malnourished patients before and after surgery, the expression of Bcl-2, Bax, NF-κB, PARP-1 was significantly lower, whereas the expression of caspases, as well as the percentage of cells with death receptors were significantly higher when compared with the control group. There was no difference in Bcl-2, Bax and PARP-1 expression between the control group and the patients with normal nutritional status (Group III) before surgery. In comparison to the standard nutrition, the preoperative immunonutrition increased the Bcl-2 and Bax expression inconsiderably but significantly increased the percentage of CD95- and CD120a-positive lymphocytes after surgery. In malnourished patients with pancreatic cancer, the overwhelming expression of caspases and the decrease expression of anti-apoptotic proteins may lead to inappropriate lymphocyte apoptosis and higher cell depletion. The preoperative enteral immunonutrition prevents the postoperative decrease in lymphocyte subsets, but a higher level of lymphocyte susceptibility to undergo accelerated apoptosis can also be considered.