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Background— No direct comparisons exist of the renal tolerability of the low-osmolality contrast medium iopamidol with that of the iso-osmolality contrast medium iodixanol in high-risk patients. Methods and Results— The present study is a multicenter, randomized, double-blind comparison of iopamidol and iodixanol in patients with chronic kidney disease (estimated glomerular filtration rate, 20 to 59 mL/min) who underwent cardiac angiography or percutaneous coronary interventions. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2 to 5 days after receiving medications. The primary outcome was a postdose SCr increase ≥0.5 mg/dL (44.2 μmol/L) over baseline. Secondary outcomes were a postdose SCr increase ≥25%, a postdose estimated glomerular filtration rate decrease of ≥25%, and the mean peak change in SCr. In 414 patients, contrast volume, presence of diabetes mellitus, use of N-acetylcysteine, mean baseline SCr, and estimated glomerular filtration rate were comparable in the 2 groups. SCr increases ≥0.5 mg/dL occurred in 4.4% (9 of 204 patients) after iopamidol and 6.7% (14 of 210 patients) after iodixanol ( P =0.39), whereas rates of SCr increases ≥25% were 9.8% and 12.4%, respectively ( P =0.44). In patients with diabetes, SCr increases ≥0.5 mg/dL were 5.1% (4 of 78 patients) with iopamidol and 13.0% (12 of 92 patients) with iodixanol ( P =0.11), whereas SCr increases ≥25% were 10.3% and 15.2%, respectively ( P =0.37). Mean post-SCr increases were significantly less with iopamidol (all patients: 0.07 versus 0.12 mg/dL, 6.2 versus 10.6 μmol/L, P =0.03; patients with diabetes: 0.07 versus 0.16 mg/dL, 6.2 versus 14.1 μmol/L, P =0.01). Conclusions— The rate of contrast-induced nephropathy, defined by multiple end points, is not statistically different after the intraarterial administration of iopamidol or iodixanol to high-risk patients, with or without diabetes mellitus. Any true difference between the agents is small and not likely to be clinically significant.