Circulating phospholipase A2(PLA2) has been recognized as a mediator of circulatory collapse in experimental endotoxic shock. To assess the role of serum PLA2in septic shock in man, we determined serum PLA2profiles in a prospective study in 12 patients with septic shock. During the hypotensive phase of sepsis, serum PLA2 levels were consistently elevated as high as 33,428 U/ml (normal range 115 ± 12 [SE]; n = 101). In all 12 patients, PLA2 levels correlated directly with the magnitude and duration of circulatory collapse (p< .001), with a progressive fall of serum PLA2levels during convalescence. In contrast, serum PLA2levels in patients with cardiogenic shock secondary to myocardial infarction remained low. In pancreatitis, PLA2levels paralleled fluctuations of serum amylase and lipase, whereas in septic shock without pancreatic involvement, PLA2changes were discordant with changes in pancreatic enzymes. As well, septic shock serum PLA2 failed to crossreact by radioimmunoassay with antiserum against human pancreatic PLA2. These data are consistent with an extrapancreatic source of intra-vascular PLA2release during sepsis. Since endogenous serum PLA2levels correlate directly with the magnitude of hypotension in both experimental endotoxic shock and clinical septic shock, and since parenteral administration of purified exogenous PLA2reproduces hypotension in experimental models, we conclude that high levels of intravascular PLA2 may contribute similarly to the circulatory collapse in septic shock in man.