Infarct volume and intracranial hemorrhage after reperfusion with nonionic low-osmolar and iso-osmolar iodinated IRCM has not been previously compared. We postulated that iso-osmolar and low-osmolar iodinated contrast media exert varied effects on cerebral infarct after intra-arterial injection. We compared infarct volume and hemorrhagic changes following intra-arterial infusion of iodixanol, iopamidol, or normal saline in a rat MCA occlusion/reperfusion model. Infarct was induced in 30 rats by a previously validated method of MCA suture occlusion. Reperfusion was performed after 5 hours with either iodixanol (n = 9), iopamidol (n = 12), or saline (n = 9). MR images were obtained at both 6 and 24 hours after ischemia, followed by sacrifice. Infarct volume was measured with T2WI and DWI by semiautomatic segmentation. Incidence and area of hemorrhage were measured on brain sections postmortem. T2WI mean infarct volumes were 242 ± 89, 324 ± 70, and 345 ± 92 mm(3) at 6 hours, and 341 ± 147,470 ± 91, and 462 ± 71 mm(3) at 24 hours in the iodixanol, iopamidol, and saline groups, respectively. Differences in infarct volume among groups were significant at 6 hours (P < .03) and 24 hours (P < .05). In the iodixanol, iopamidol, and saline groups, mean areas for cortical intracranial hemorrhage were 0.8, 18.2, and 25.7 mm(2); and 28, 31, and 56.7 mm(2), respectively, for deep intracranial hemorrhage. The differences in intracranial hemorrhage area among groups were statistically significant for cortical intracranial hemorrhage (P < .01). Intra-arterial infusion of nonionic iso-osmolar iodixanol showed reduced infarct volume and reduced cortical intracranial hemorrhage areas in comparison with nonionic low-osmolar iopamidol and saline. Our results may be relevant in the setting of intra-arterial therapy for acute stroke in humans, warranting further investigation.