AIMS: Baseline body mass index (BMI) and weight loss promoted by sodium-glucose cotransporter 2 inhibitors may impact outcomes in patients with heart failure with reduced ejection fraction (HFrEF). We assessed in the EMPEROR-Reduced population treated with empagliflozin versus placebo the relationship between baseline BMI, weight loss and effects on the primary (time to first hospitalization for heart failure [HHF] or cardiovascular death) and key secondary outcomes. METHODS AND RESULTS: We categorized patients according to their baseline BMI: <20 kg/m2 (n = 180); 20 to <25 kg/m2 (n = 1038); 25 to <30 kg/m2 (n = 1345); 30 to <35 kg/m2 (n = 774) and ≥35 kg/m2 (n = 393). The treatment effect of empagliflozin on the primary outcome was consistent across all BMI categories (hazard ratios in subgroups 0.66-0.88, interaction trend p = 0.32), as was the effect on total (first plus recurrent) HHF (interaction trend p = 0.31). Empagliflozin reduced the rate of estimated glomerular filtration rate decline consistently across the BMI categories (interaction trend p = 0.67). Overall, incidence rates of any or serious adverse events were comparable between the treatment groups across all BMI categories. A total of 313 (17.4%) patients treated with empagliflozin experienced a weight loss of more than 5% at week 52 versus 230 (12.8%) in placebo. When analysed separately within each treatment group, presence of weight loss was similarly associated with an increased risk of all-cause mortality. CONCLUSION: The benefits of empagliflozin versus placebo were consistently present across all BMI categories in HFrEF patients. Weight loss was associated with higher risk of all-cause mortality, regardless of treatment group.