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Background. Diabetic patients presenting with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) have an increased risk of contrast-induced-acute kidney injury (CI-AKI). It has been shown that sodium-glucose cotransporter-2 inhibitors (SGLT2-I) have a nephroprotective effect. Purpose. To analyze the association between chronic SGLT2-I treatment and the development of CI-AKI in diabetic patients with AMI (both ST- and non-ST segment elevation myocardial infarction) treated with PCI, in both patients with and without chronic kidney disease (CKD). Methods. In this multicenter international registry, consecutive patients with type 2 diabetes mellitus (T2DM) and AMI undergoing PCI between 2018 and 2021 were enrolled. The study population was stratified by the presence of CKD and anti-diabetic therapy at admission (SGLT2-I versus non-SGLT2-I users). CI-AKI was defined as an absolute (≥0.5 mg/dl) or relative increase (≥25%) in creatinine at 48-72 h after PCI compared to baseline values. Results. The study population consisted of 646 AMI patients: 111 SGLT2-I users [28 (25.2%) with CKD] and 535 non-SGLT2-I users [221 (41.3%) with CKD]. The median age was 70 [61-79] years, and more than 77% were males. Independently of creatinine at admission, SGLT2-I users exhibited significantly lower creatinine values at 72h after PCI, both in the non-CKD and CKD stratum. After PCI, the overall rate of CI-AKI was 76 (11.8%), significantly lower in SGLT2-I users compared to non-SGLT2-I patients (5.4% vs 13.1%, p=0.022). This finding was confirmed also in patients without CKD (p=0.040). In the CKD cohort, SGLT2-I users maintained significantly lower creatinine values at discharge, albeit without significant differences in CI-AKI rate compared to non-SGLT2-I patients. At multivariate analysis, the use of SGLT2-I was identified as an independent predictor of reduced rate of CI-AKI (OR 0.356; 95%CI 0.134-0.943, p=0.038). Patients with CI-AKI reported a longer hospital stay and higher incidence of adverse cardiovascular events at follow-up (p=0.001), mostly in the CKD cohort. Conclusion. In T2DM patients with AMI, the use of SGLT2-I was associated with a lower risk of CI-AKI during the index hospitalization, mostly in patients without CKD. Our results provide new insights into the cardio and nephroprotective effects of SGLT2-I in the setting of AMI. Trial Registration: data are part of the observational Registry: SGLT2-I AMI PROTECT. ClinicalTrials.gov Identifier: NCT 05261867.