Background: An impaired host immuninity might concur in determining the tremendous prognosis of pancreatic cancer (PC). Our aim was to ascertain whether the pattern of blood lymphocytes immunophenotype in PC correlates with: (1) tumor stage, (2) tumor grade, (3) the development of metastases after surgery, (4) survival. Patients and Methods: We studied 46 PC patients. Staging was: stage I 2.2%, stage II 8.9%, stage III 48.9%, stage IV 40.0%. Grading was: G1 19.4%, G2 47.2%, G3 33.3%. Survival was available for 32 patients (minimum 1, maximum 24, median 19 months). Metastases were found after surgery in 76% of these patients. Lymphocyte immunophenotype was determined by FACS analysis. The following were considered: CD16/CD56 (natural killer), CD19 (B lymphocytes), CD3 (T lymphocytes), CD4 (T helper), CD8 (T cytotoxic). Results: Tumor stage did not correlate with lymphocytes immunophenotype or total lymphocyte count. CD16/56 were lower in patients with (14.7% 1.14, mean SE) than in those without lymphnode metastases (25.4% 4.9) (t 9.83, p 0.01). CD4 were lower in patients with undifferentiated (47.6% 2.1) than in those with well differentiated PC (55.6% 2.1) (t 2.65, p 0.05). Tumor stage, not grade (2 3.55, p:ns), correlated with the development of metastases after surgery (2 12.75, p 0.01). Patients who developed distant metastases after surgery had also significantly lower levels of total lymphocytes (Mann Whitney U 31.5, p 0.05). Total lymphocyte count discriminated patients who developed from patients who did not develop distant metastases after surgery with a sensitivity of 75% and a specificity of 64% (cutoff 1.5 109/L). The overall survival of patients correlated with tumor stage (Log rank 12.4, p 0.01), but also with total lymphocytes (Log rank 16.5, p 0.001). The association between survival and total lymphocyte count was confirmed when stage III (Log rank 10.2, p 0.005) or stage IV patients (Log rank 3.0, p 0.08) were considered singly. Conclusions: The presence of lymphnode metastases at diagnosis or the development of metastases after surgery are significantly associated with a reduction of natural killer cells and total lymphocytes counts. A reduction in the latter at diagnosis could predict patients’ survival, indendently from tumor stage.