| Summary: | (1) <b>Background</b>: This single-center retrospective study aimed to evaluate whether sodium–glucose cotransporter-2 inhibitors (SGLT2-i) therapy may have a nephroprotective effect to prevent contrast-induced acute kidney injury (CI-AKI) in patients with heart failure (HF) undergoing iodinated contrast medium (ICM) invasive procedures. (2) <b>Methods</b>: The population was stratified into SGLT2-i users and SGLT2-i non-users according to the chronic treatment with gliflozins. The primary endpoint was CI-AKI incidence during hospitalization. Secondary endpoints were all-cause mortality and the need for continuous renal replacement therapy (CRRT). (3) <b>Results</b>: In total, 86 patients on SGLT2-i and 179 patients not on SGLT2-i were enrolled. The incidence of CI-AKI in the gliflozin group was lower than in the non-user group (9.3 vs. 27.3%, <i>p</i> < 0.001), and these results were confirmed after propensity matching analysis. Multivariable logistic regression showed that only SGLT2-i treatment was an independent preventive factor for CI-AKI (OR: 0.41, 95% CI: 0.16–0.90, <i>p</i> = 0.045). The need for CRRT was reported only in five patients in the non-SGLT2-i-user group compared to zero patients in the gliflozin group (<i>p</i> = 0.05). (4) <b>Conclusions</b>: SGLT2-i therapy was associated with a lower risk of CI-AKI in patients with HF undergoing ICM invasive procedures.
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