The effect of hypofibrinogenemia on production of the generalized Shwartzman reaction (GSR) by the administration of Thorotrast (3 ml/kg) and Escherichia coli endotoxin (50 µg) to rabbits was determined. Severe hypofibrinogenemia (fibrinogen less than 15 mg/ 100 ml) was produced by Arvin, a proteolytic coagulant from the venom of the Malayan pit viper, Agkistrodon rhodostoma. Development of the GSR was inhibited significantly only when hypofibrinogenemia was produced 30 hr before the preparatory injection of Thorotrast and maintained for the duration of the experiment. Severe hypofibrinogenemia of 2-20-hr duration before administration of endotoxin did not block the production of the GSR. Elevated levels of fibrinogen degradation products were demonstrated in the serum of all animals that received Arvin. The concentration of fibrinogen degradation products decreased markedly prior to death only in those animals that developed the GSR. The GSA was not observed in rabbits that received only Thorotrast and Arvin, although these animals had the highest levels of fibrinogen degradation products. The data suggest an essential role for fibrinogen or fibrinogen degradation products and endotoxin in the production of the GSR.