Acute kidney injury (AKI) after percutaneous coronary intervention (PCI) is associated with worse outcomes. Consecutive patients undergoing PCI between 2005 and 2013 were retrospectively analyzed. Patients undergoing PCI using transfemoral access (TFA) were categorized as the TFA Group, and those using transradial access (TRA) were categorized as the TRA Group. Post-PCI AKI was defined as an increase in serum creatinine >0.5 mg/dl or >25% increase from baseline 48 to 72 hours after the procedure. Independent predictors of post-PCI AKI were identified using inverse probability weighted multivariable analysis. There were 7,529 patients included in the analysis, 5,353 (71%) in the TFA Group and 2,176 (29%) in the TRA Group. Patients in the TRA Group were younger, more likely to be female, taller, heavier and have acute coronary syndrome (ACS) and were less likely to have previous coronary artery bypass graft surgery, cardiogenic shock, and intra-aortic balloon pump use and had shorter fluoroscopy time and less contrast use. Bleeding Academic Research Consortium type 3 or 5 was significantly less frequent in the TRA Group. The primary end point of post-PCI AKI was observed significantly less frequently in the TRA Group compared with the TFA Group (1.1% vs 2.4%, p = 0.001). TRA was independently associated with a lower incidence of post-PCI AKI (odds ratio 0.57, 95% confidence interval 0.35 to 0.91, p = 0.018). In conclusion, access site choice is an independent predictor of post-PCI AKI with a significant risk reduction associated with TRA compared with TFA.