High levels of circulating phospholipase A2 (PLA2) have been implicated in the pathogenesis of hypotension in experimental endotoxin shock. In an attempt to detect similar mechanisms in clinical gram-negative septic shock, plasma samples from 34 patients with hypotension and septicemia were collected and assayed for PLA2 activity. PLA2 levels in 100% of patients with septic shock were elevated (as high as 43-fold over control levels), and mean plasma PLA2 activity was increased 16-fold over control levels. Those patients with concurrent adult respiratory distress syndrome had a mean plasma PLA2 activity level 20.2-fold greater than did controls and 44% greater than patients whose clinical courses were not complicated by adult respiratory distress syndrome. In patients who survived the hypotensive episode, follow-up determinations during the convalescent phase showed a return in plasma PLA2 levels to baseline values. Using pooled plasma, preliminary molecular weight determination revealed the PLA2 to be a 14,000-dalton lipolytic enzyme with 2-acyl specificity. Our study composes the first demonstration of markedly elevated levels of plasma PLA2 during septic shock. Because circulating PLA2 had been shown experimentally to cause profound systemic hypotension and degradation of pulmonary surfactant, this suggests a mechanistic relationship between the massive release of PLA2 into the systemic circulation during the course of gram-negative septicemia, and the resultant hypotension and respiratory distress syndrome associated with gram-negative septic shock.