A transient iridocyclitis is produced in rabbits by the intravenous injection of bacterial endotoxin. A major feature of this response is an altered vascular permeability which can be measured by the ocular accumulation of circulating 125I-labeled albumin. The present study was made to determine the effects of inhibitors of prostaglandin synthesis of the ocular response to an E. coli 055:B5 endotoxin. Aspirin pretreatment prevented the ocular response following the intravenous injection of 10 mug per kilogram of endotoxin, but had no effect following 100 mug per kilogram. Indomethacin pretreatment prevented an alteration in ocular vascular permeability 1 1/2 hours after the injection of 100 mug per kilogram of endotoxin and significantly reduced the alteration 4 hours after endotoxin. Thus inhibitors of prostaglandin synthesis can prevent the ocular response to circulating endotoxin depending on their relative potency and the amount of injected endotoxin. These results suggest that prostaglandins are important in the ocular response to circulating endotoxin in the rabbit.