Background In the absence of randomized studies, it has been controversial whether the likelihood of acute kidney injury (AKI) differs between intravenous and intra-arterial contrast agent administration. Purpose To compare intravenous versus intra-arterial contrast agent administration in relationship to AKI and analyze the association between AKI and chronic kidney disease (defined as at least mildly decreased estimated glomerular filtration rates [eGFRs]). Materials and Methods This was a prospective study (ClinicalTrials.gov: NCT00844220) that involved randomizing participants with atypical chest pain and suspected coronary artery disease (CAD) between February 2009 and August 2015 to undergo coronary CT angiography with intravenous contrast agent administration or cardiac catheterization angiography with intra-arterial contrast agent administration. This prespecified secondary analysis compared AKI (serum creatinine increase of ≥ 25% or 0.5 mg/dL after 18-24 or 46-50 hours) determined by blinded investigators using absolute differences and relative risks, including two-sided 95% confidence intervals (CIs). Results A total of 320 participants (163 [50.9%] women; mean age, 60 years ± 11) were included. Baseline eGFR did not differ between the CT angiography group (84.3 mL/min/1.73 m2 ± 17.2) and the catheterization group (87.1 mL/min/1.73 m2 ± 16.7) (P = .14). AKI occurred in nine of 161 participants in the CT angiography group (5.6%; 95% CI: 3%, 10%) and in 21 of 159 participants in the catheterization group (13.2%; 95% CI: 9%,19%) (relative risk, 2.4; 95% CI: 1.1, 5.0; P = .02). Also in the subgroup of participants without obstructive CAD, in those not requiring coronary interventions, AKI was more common in the catheterization group (11.9%; 95% CI: 8%, 19%) than in the CT angiography group (4.3% [95% CI: 2%, 9%]; difference, 7.7% [95% CI: 1.3%, 14.1%]; relative risk, 2.8 [95% CI: 1.1, 7.0]; P = .02). Obstructive CAD (odds ratio [OR]: 2.7 [95% CI: 1.1, 6.6]; P = .02), femoral catheter access (OR: 2.5 [95% CI: 1.1, 5.6]; P = .04), and cine ventriculography were associated with AKI (OR: 2.3 [95% CI: 1.0, 4.9]; P = .03). In multivariable analysis, the presence of postcontrast AKI was associated with chronic kidney disease (hazard ratio: 12.4 [95% CI: 4.5, 34.6]; P < .01). Conclusion Acute kidney injury was more common after cardiac catheterization than after CT angiography in this prospective randomized study of patients suspected of having coronary artery disease. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Einstein and Newhouse in this issue.