Acute necrotizing pancreatitis (ANP), which often progresses to infection, sepsis, and multisystem organ failure, runs a course remarkably similar to that seen frequently after severe burns, massive physical trauma, or major surgery. There is extensive evidence that the development of the sepsis response is mediated by immunocytes, particularly activated polymorphonuclear leukocytes (PMNLs) and their secretions (reactive oxygen species, lysosomal hydrolases, cytokines, and so on). Some years ago it was suggested that the high mortality of ANP may be related to an overaggressive immunological defense system of the host rather than to autodigestion of the gland. Recent investigations of the immunoregulatory responses following surgery or other trauma have not only furnished additional support for this concept, but also revealed some genetic factors that may critically influence the outcome of posttraumatic illness including ANP. The prognostic significance of abnormal, early polymorphonuclear leukocyte (PMNL) activation in the development of sepsis, high neutrophil expression of certain receptor molecules, low monocyte and lymphocyte expression of major histocompatibility antigen MHC-class II, and the influence of the genetically encoded TNF and IL-1 secretion on the course of the illness are discussed and related to ANP. Evidence is presented for the potential usefulness of some of these parameters in the prognosis and future treatment of ANP.