Cancer patients have not been included in landmark trials of SGLT2is in heart failure, so data on safety and effectiveness are lacking. TOSCA is a multi-center observational trial including patients with active cancer receiving SGLT2is for HF treatment. The primary endpoint was safety, and the secondary endpoint was effectiveness. Exploratory endpoints included drug–drug interactions, treatment of cancer therapy-related cardiac dysfunction (CTRCD), and changes in NT-proBNP. One-hundred and twenty-nine patients (median age 72 [range 44–92] yrs) were enrolled who had been receiving SGLT2i for a median of 3 (range 3–25) months. Prevalent etiology was drug-induced HF with HFrEF as the most frequent clinical presentation. The incidence of urinary tract infections was 1.8%, with no cases of genital infections, hypoglycemia, diabetic ketoacidosis, acute renal injury, thrombosis, or bone fractures. The mean overall EF increased (40.3% vs. 47.4%), and NYHA class improved in 19% of cases. Rates of unplanned cardiology visits (0.9%), use of i.v. diuretics (0.9%), coronary angiography (4.5%), emergency access for HF (1.8%), and new HF episodes (3.6%) were extremely low. In 11 cases (8.5%), the initiation of SGLT2i enabled continuation of anticancer therapy that would have otherwise been delayed or suspended due to HF decompensation. SGLT2is appeared effective in 34 cases of CTRCD. No drug–drug interactions were reported. SGLT2is confirmed their safety and effectiveness in active cancer patients with HF, with a potential cardioprotective effect. No new safety warnings were recorded.