Background: An abnormal immune response may play a pathogenetic role in chronic pancreatitis. However, to date characterization of the systemic immunological changes in patients with chronic pancreatitis has not been undertaken. Methods: Lymphocyte phenotypes and proliferation (3H-thymidine) after stimulation with mitogens and interleukin-2 were studied in peripheral mononuclear cells from 11 patients with chronic pancreatitis (alcohol-induced n = 6; idiopathic pancreatitis n = 5). The natural killer cell activity was investigated in a 51Cr release cytotoxicity assay. In vitro cytokine release of stimulated mononuclear cells was measured. Results: Flow cytometric studies showed a significant decrease in the percentage of circulating CD8+, CD56+ and CD25+ cells in patients with chronic pancreatitis independent of the etiology. Comparing all patients with chronic pancreatitis to controls, the proliferation rate was not significantly increased, but patients with pain (n = 5) showed increased proliferation in comparison to patients without pain (n = 6). No significant difference in natural killer cytotoxicity was observed. The in vitro release of tumor necrosis factor-α and interleukin-10 by stimulated mononuclear cells was increased. Conclusions: Chronic pancreatitis is accompanied by systemic immune dysregulation. The observed changes in peripheral mononuclear cells reveal additional evidence that the cell-mediated immune response may contribute to the development of pain and tissue destruction in chronic pancreatitis.