The cellular mechanisms involved in the pathogenesis of atherosclerosis may be similar to the events in the inflammatory response. Many of these processes are activated by the arachidonic acid cascade. The nonsteroidal anti-inflammatory drugs inhibit the cycloxegenase and possibly the lipoxegenase pathways, decreasing the production of prostaglandins, thromboxanes, and leukotrienes, all components of the inflammatory process. We have inhibited the arachidonic acid cascade with the nonsteroidal anti-inflammatory drugs, indomethacin (5 mg/kg/day) and phenylbutazone (10mg/kg/day). Forty-five New Zealand white rabbits were given a 0.25% cholesterol diet for 16 weeks in addition to the drugs or a placebo. Serial plasma lipid profiles were performed; aortic and peripheral arterial cholesterol content measurements were obtained at sacrifice. All groups showed markedly elevated plasma lipids. Thoracic aortic and carotid artery cholesterol contents were significantly decreased in both treated groups as compared to placebo (P < 0.05), despite the atherogenic lipid profiles. These results implicate the immune and inflammatory responses in the pathogenesis of atherogenesis.