We sought to compare the nephrotoxicity of the iso-osmolar contrast medium, iodixanol, to low-osmolar contrast media (LOCM). Contrast-induced acute kidney injury (CI-AKI) is a common cause of in-hospital renal failure. A prior meta-analysis suggested that iodixanol (Visipaque, GE Healthcare, Princeton, New Jersey) was associated with less CI-AKI than LOCM, but this study was limited by ascertainment bias and did not include the most recent randomized controlled trials. We searched Medline, Embase, ISI Web of Knowledge, Google Scholar, Current Contents, and International Pharmaceutical Abstracts databases, and the Cochrane Central Register of Controlled Trials from 1980 to November 30, 2008, for randomized controlled trials that compared the incidence of CI-AKI with either iodixanol or LOCM. Random-effects models were used to calculate summary risk ratios (RR) for CI-AKI, need for hemodialysis, and death. A total of 16 trials including 2,763 subjects were pooled. There was no significant difference in the incidence of CI-AKI in the iodixanol group than in the LOCM group overall (summary RR: 0.79, 95% confidence interval [CI]: 0.56 to 1.12, p = 0.19). There was no significant difference in the rates of post-procedure hemodialysis or death. There was a reduction in CI-AKI when iodixanol was compared with ioxaglate (RR: 0.58, 95% CI: 0.37 to 0.92; p = 0.022) and iohexol (RR: 0.19, 95% CI: 0.07 to 0.56; p = 0.002), but no difference when compared with iopamidol (RR: 1.20, 95% CI: 0.66 to 2.18; p = 0.55), iopromide (RR: 0.93, 95% CI: 0.47 to 1.85; p = 0.84), or ioversol (RR: 0.92, 95% CI: 0.60 to 1.39; p = 0.68). This meta-analysis including 2,763 subjects suggests that iodixanol, when compared with LOCM overall, is not associated with less CI-AKI. The relative renal safety of LOCM compared with iodixanol may vary based on the specific type of LOCM.