Hyperlipidemia is an identified risk factor for atherosclerosis in patients following renal transplantation that may be related to previous uremia and various drugs including steroids. Recent evidence has suggested that treatment with cyclosporine may be an independent risk factor for development of hyperlipidemia in some patients. Twenty-four Sprague Dawley rats were given CsA at 30 mg/kg by gavage for 28 days in 1 ml of olive oil or fish oil vehicle, and compared with controls receiving just vehicle. Increases of both triglyceride (233.6%) and cholesterol (50.9%) were observed in olive oil/CsA animals (P less than .01), with no significant change noted with either vehicle alone. An increase of triglyceride from baseline was observed with fish oil/CsA (119%) (P less than .01) but was significantly less than the increase with olive oil/CsA animals (P less than .05). No increase in cholesterol was found in CsA-treated rats using the fish oil vehicle. The mechanisms leading to hyperlipidemia with four weeks of CsA administration in these rats are unknown, but may be related to altered hepatic synthesis. CsA levels were lower in fish oil-treated animals, possibly explaining the difference noted in lipid levels--or, alternatively, reduction of plasma lipoproteins may have altered drug kinetics and CsA binding. This work emphasizes a need for further study of lipids in CsA-treated patients, and advises some caution in the use of lipoprotein-reducing agents in patients using CsA without consideration of the possible effect on free drug levels.