Massive elevations of serum phospholipase A2 activity have been documented in patients with septic shock. Serum PLA2 activity correlated to the degree and duration of circulatory collapse, while purified native PLA2 reproduced hypotension in experimental animals. In a prospective study of patients with septic shock, we have determined the relationship of PLA2 enzyme activity to PLA2 immunoreactivity using radiolabelled E. coli phospholipid substrate and an ELISA specific for group II human nonpancreatic PLA2. In all patients, there was a clear concordance of the two assays. Maximal PLA2 concentration was increased a mean of 554-fold over normal levels. We found no evidence to support the presence of activating or inhibitory proteins. These data confirm that the observed increase in serum PLA2 activity in septic shock is due to intravascular release of group II nonpancreatic PLA2.