Abstract Background Chronic therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i) is associated with long term reno-protective benefits. There are limited data on the benefits of these agents against the risk of contrast-associated acute kidney injury (CA-AKI). Purpose The goal of our study was to assess the comparative efficacy of SGLT2i for the prevention of CA-AKI in diabetic patients undergoing PCI. Methods The study population included all diabetic patients enrolled in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium Percutaneous Coronary Intervention (BMC2PCI) registry, a clinical registry of all PCI cases at non-federal hospitals in the state of Michigan, USA. Included patients underwent PCI between January 2022 and September 2023. Patients on dialysis were excluded. Predicted AKI risk was calculated using a previously validated and published machine learning BMC2 risk model. The primary outcome of CA-AKI was defined as an elevation in serum creatinine of ≥0.5 mg/dL following PCI. Risk-adjusted AKI rates were estimated by the product of event observed/expected ratio and overall collaborative AKI rate. Propensity matching on 23 covariates was used to adjust for the non-random use of SGLT2i. Results A total of 19,078 diabetic patients were included, of whom 3,087 (16.2%) were prescribed SGLT2i prior to PCI. Patients treated with SGLT2i were younger (66.1 vs 68.3 years), more likely to be men (73.3% vs 65.3%), have heart failure (50.4% vs 42.4%), have prior PCI (58.4% vs 48.8%), and have co-prescription of insulin (43.8% vs 37.3%) (p<0.001 for all). After propensity matching, no significant baseline difference between cohorts remained, with an absolute standardized difference less than 10% on all covariates. The pre-procedural use of SGLT2i was associated with a lower incidence of CA-AKI in unadjusted analysis (2.7% vs 3.8%, p=0.003) and after adjusting for the baseline predicted risk of CA-AKI (2.2% vs 2.8%, adjusted OR 0.69, 95% CI 0.54-0.89, p=0.0045). In a propensity-matched analysis, the use of SGLT2i was strongly associated with a reduced adjusted risk for CA-AKI (2.2 % vs 2.8%, adjusted OR 0.72, 95% CI 0.62-0.84, p=0.026). Conclusions Among patients with diabetes presenting for PCI, pre-procedural use of SGLT2i was associated with a significant reduction in the risk of CA-AKI. These results should compel further investigation into the beneficial effects of SGLT2 inhibitors in reducing the risk of CA-AKI.