Based on earlier studies in rats, phospholipase C (PLC) seemed to be a very promising prophylactic agent for certain types of thrombo-embolic disease. Recent studies in rabbits have, however, demonstrated that phospholipase C is more toxic than expected from the previous data. To gain more knowledge about its toxicity in larger animals we have studied its effect in sheep. Estimated LD50 for the enzyme in sheep was between 0.4 and 0.2 mg PLC/kg given as a 23 min infusion and below 0.2 mg/kg given as a bolus. Cellular necrosis was a common feature in several tissues of sheep dying from PLC. This explained the pulmonary oedema, decreased oxygen tension and renal failure with haematuria, proteinuria and glucosuria which occurred. PLC was probably filtered out in the glomeruli and totally reabsorbed in the tubuli until they were destroyed by PLC. An increase in different plasma enzymes suggested that PLC exerted a toxic effect on both muscle cells and hepatocytes. The blood glucose level remained about 20% lower in the PLC-treated animals than in the controls for more than 2 weeks. Pulmonary oedema and renal failure were the probable causes of death.