Sodium arachidonate given intravenously at a dose of 2 mg/kg is uniformly lethal in rabbits. Rabbits die within 2-5 min following a dramatic decrease in mean arterial blood pressure (MABP), and in circulating platelets, and a large increase in plasma thromboxane B2 (TxB2) concentration. The nonsteroidal anti-inflammatory agent, ibuprofen, given 15 min prior to challenge with sodium arachidonate, significantly protects against the abrupt decrease in MABP and in circulating platelets and prevents the increase in circulating TxB2 concentrations. These rabbits all survive the lethal effects of arachidonic acid when given ibuprofen at doses of 0.75, 6.25 or 12.5 mg/kg intravenously 15 min prior to arachidonate challenge. At 0.375 mg/kg, only 20% of the animals survive. Concomitant with survival is a significant attenuation of the decrease in MABP (84 +/- 8 mm Hg without ibuprofen vs. 1 +/- 1 to 33 +/- 12 mm Hg with 12.5-0.75 mg/kg ibuprofen). Similarly, these rabbits show a greatly reduced loss of circulating platelets, and virtually no increases in the formation of TxB2. Ibuprofen protects against arachidonate-induced sudden death in a dose-related manner. The mechanism of the protection appears to involve prevention of adherence or aggregation of platelets and the subsequent formation of thromboxane A2. The net result is prevention of pulmonary thrombosis, the major pathological event in triggering sudden death.