Objective: Bacterial and fungal associated infections are common complications of severe acute pancreatitis (AP), suggesting that the innate immune response is impaired during the disease process. This study aims to characterize aspects of the systemic innate immune response within two experimental models of AP. Aims: To determine the rates of apoptosis and necrosis of peripheral blood leukocytes during an episode of severe AP; and To determine the phagocytic capacity of peripheral blood leukocytes during an episode of severe AP. Methods: Severe AP was induced in rats using either intraperitoneal arginine or caerulein injections. 90 Fischer/Lewis rats were randomized to 3 groups (arginine, caerulein, control). AP was confirmed on the basis of biochemistry and histology. At fixed time points between day 1 and day 14 post induction, peripheral blood leukocyte function was determined. Leukocyte apoptosis and necrosis was quantified using YOPRO/7AAD and AnnexinV/PI. The ability of leukocytes to phagocytose Escherichia coli was quantified using flow cytometric technique. Appropriate ANOVA techniques were performed for statistical analysis. Results: Following induction of AP with caerulein, the rates of both apoptosis and necrosis of peripheral blood granulocytes demonstrated a triphasic pattern with a significant increase on day 1 (vs. control p=0.011), followed by a fall on day 3 (p<0.05) with a further increase in rates on day 10 (vs. other time-points p<0.05). This triphasic pattern was not observed following induction with arginine, although a trend of increased necrosis of granulocytes was observed after day 7. Following induction of AP with caerulein, the rate of lymphocyte apoptosis initially fell but became elevated by day 10, which was statistically significant as compared to other time-points (p<0.02). In comparison, induction with arginine led to an early increase in the rate of necrotic cell death of lymphocytes but had no effect on late lymphocyte loss. In both models of AP the rates of granulocyte phagocytosis were significantly reduced at day 7 (H(2)=8.29, p=0.016) but not at other time points. Conclusion: Experimental acute pancreatitis is associated with significant changes in systemic innate immune function. These changes may, in part, depend on the agent used to induce acute pancreatitis. The present observation of an increase in late leukocyte apoptosis and necrosis, coupled with reduced leukocyte phagocytic ability, suggests a reason why patients with acute pancreatitis are at increased risk of septic complications.