Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the combined risk of death and hospitalization in patients with heart failure with reduced or preserved left ventricular ejection fraction. However, evidence of their impact on patients with heart failure due to amyloidosis is lacking. Purpose To evaluate the effects of SGLT2 inhibitors on mortality and hospitalization in patients with amyloidosis and heart failure. Methods In this retrospective cohort study, we used real-world data from 108 healthcare organizations worldwide from the global health research collaborative network TriNetX. We identified 24,619 patients with amyloidosis and heart failure without exposure to SGLT2 inhibitors (control group) and 2,988 patients with amyloidosis and heart failure under treatment with SGLT2 inhibitors (SGLTi group). We performed propensity score matching for demographic and clinical characteristics and Kaplan–Meier plots, log-rank tests, and Cox proportional hazard models were calculated. The outcomes were 12-month all-cause death and 12-month hospitalization. Results After propensity score matching, 2,237 patients were analyzed in each group. During the 12-month follow-up, 198 (8.8%) patients died in the SGLT2i group, and 431 (19.2%) patients died in the control group (hazard ratio 0.51, 95% CI 0.43-0.61). In the SGLT2i group, 974 (44.5%) patients were hospitalized, and in the control group, 1508 (53.5%) patients were hospitalized (hazard ratio 0,79, 95% CI 0.72-0.86). The Kaplan-Meier curves are shown in Figure 1. Conclusions In conclusion, in this retrospective cohort study with a large number of patients with amyloidosis and heart failure, SGLT2 inhibitors were associated with a lower 12-month all-cause mortality and hospitalization. Further evidence from randomized controlled studies are needed to confirm the efficacy of SGLT2 inhibitors in patients with cardiac amyloidosis.Figure 1.Kaplan-Meier curves