Radiocontrast nephropathy (RCN) is a common clinical problem without effective therapy. Utilizing a murine model, we tested the hypothesis that alpha-2 adrenergic receptor agonists [clonidine, dexmedetomidine (dex)] protect against RCN, induced with iohexol (a nonionic low-osmolar radiocontrast). C57BL6 mice were pretreated with saline, clonidine, or dex before induction of RCN. Some mice were pretreated with yohimbine (a selective alpha-2 receptor antagonist) prior to saline, clonidine or dex administration. Alpha-2 agonist treated mice had reduced plasma creatinine, renal tubular necrosis, renal apoptosis, and renal cortical proximal tubule vacuolization 24 hrs after iohexol injection. Yohimbine reversed the protective effects of both clonidine and dex pretreatment. Injection of iohexol resulted in a rapid (~90 min.) fall of renal outer-medullary blood flow. Clonidine and dex pretreatment significantly attenuated this perfusion decrease without any changes in systemic blood pressure. To determine whether proximal tubular alpha-2 adrenergic receptors mediate the cytoprotective effects, we treated cultured human proximal tubule (HK-2) and rat pulmonary microvascular endothelial cells (RPMEC) with iohexol after vehicle, clonidine or dex pretreatment. Iohexol caused a direct dose-dependent reduction in HK-2 and RPMEC viability, but alpha-2 agonists failed to preserve the viability of both cell types. We conclude that alpha-2 adrenergic receptor agonists protect mice against RCN by preserving outer-medullary renal blood flow. As alpha-2 agonists are widely utilized during the perioperative period, our findings may have significant clinical relevance to improving outcomes following radiocontrast exposure.