Background: It has been suggested that aldosterone, with its known pro-inflammatory and profibrotic actions, may play a key role in the development and progression of atherosclerosis. METHOD: In this study, the ability of aldosterone antagonism to reduce atherosclerosis in experimental diabetes was assessed. Diabetes was induced in ApoE knockout mice with streptozotocin, and the mice were treated with the specific aldosterone antagonist, eplerenone, in their feed over 20 weeks (∼200 mg/kg per day). Result: En face analysis revealed that eplerenone treatment was unable to attenuate atherosclerosis as assessed by percentage lesion area quantitation in the aortae of these mice compared with untreated diabetic mice (diabetic, 10.7 ± 1.1; diabetic + eplerenone, 8.8 ± 1.2%). In contrast, we observed a significant, more than 50% decrease in percentage of plaque area in the nondiabetic control groups. Despite this lack of effect in the diabetic mice, eplerenone treatment was associated with reduced cytosolic superoxide production. However, aortic transcript levels of key molecules implicated in diabetes-associated atherogenesis, such as monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1, were not significantly attenuated by eplerenone. Conclusion: These findings suggest that eplerenone treatment may not be as antiatherosclerotic in the diabetic context.