Background: Sodium/glucose cotransporter-2 inhibitors (SGLT2is), such as dapagliflozin and empagliflozin, are currently a standard therapy for heart failure (HF) patients. We report the real-world use of SGLT2is in a monocentric cohort of HF patients with reduced ejection fraction (HFrEF) and improved ejection fraction (HFimpEF), comparing patient characteristics and outcomes with those observed in large-scale randomized clinical trials (RCTs). Methods: We retrospectively analyzed a cohort of 370 stable patients with HFrEF or HFimpEF who initiated therapy with dapagliflozin or empagliflozin between June 2019 and November 2023. Baseline data, including medical history, concomitant diseases, therapy, laboratory tests, echocardiographic results and cardiopulmonary exercise tests (CPETs), were collected at the start of the therapy with SGLT2is. After a median period of 18 months, follow-up data on treatment adherence, adverse events, hospitalizations, and mortality were also reviewed. A comparison was made between patients taking dapagliflozin and those taking empagliflozin and then individual populations were compared with those from the trials. Results: Among 370 patients (81% HFrEF, 19% HFimpEF), 276 received dapagliflozin and 94 empagliflozin. Empagliflozin patients were older, had higher NYHA class and LVEF, and higher incidence of diabetes, while dapagliflozin users had greater use of sacubitril/valsartan and mineralocorticoid receptor antagonists. Both groups were older than the RCT cohorts. Dapagliflozin patients had LVEF comparable to DAPA-HF, while empagliflozin patients had higher LVEF than EMPEROR-Reduced. HF hospitalizations were more frequent in the real-world groups, but mortality was lower than in RCTs. The composite outcome of death and worsening HF was higher in the real-world dapagliflozin cohort vs. DAPA-HF but similar between the real-world empagliflozin cohort and EMPEROR-Reduced. Conclusions: In this real-world cohort, the use of empagliflozin was associated with cardio-nephro-metabolic comorbidities and dapagliflozin being prescribed more frequently for patients with isolated cardiac symptoms. While outcomes were generally favorable, they differed from those seen in RCTs, highlighting the importance of real-world data in understanding the practical application of these therapies.