Abstract Background Guideline recommendations for the treatment of heart failure with mildly reduced ejection fraction (HFmrEF) derive from small subgroups in post-hoc analyses of randomized trials. Objectives We investigated predictors of renin–angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI) and beta-blockers use, and the associations between these medications and mortality/morbidity in a large real-world cohort with HFmrEF. Methods and results Patients with HFmrEF (EF 40–49%) from the Swedish HF Registry were included. The associations between medications and cardiovascular (CV) mortality/HF hospitalization (HFH), and all-cause mortality were assessed through Cox regressions in a 1:1 propensity score-matched cohort. A positive control analysis was performed in patients with EF < 40%, while a negative control outcome analysis had cancer-related hospitalization as endpoint. Of 12 421 patients with HFmrEF, 84% received RASI/ARNI and 88% beta-blockers. Shared-independent predictors of RASI/ARNI and beta-blockers use were younger age, being an outpatient, follow-up in specialty care, and hypertension. In the matched cohorts, use of both RASI/ARNI and beta-blocker use was separately associated with lower risk of CV mortality/HFH [hazard ratio (HR) = 0.90, 95% confidence interval (CI): 0.83–0.98 and HR = 0.82, 95% CI: 0.74–0.90, respectively] and of all-cause mortality (HR = 0.75, 95% CI: 0.69–0.81 and HR = 0.79, 95% CI: 0.72–0.87, respectively). Results were consistent at the positive control analysis, and there were no associations between treatment use and the negative control outcome. Conclusions RASI/ARNI and beta-blockers were extensively used in this large real-world cohort with HFmrEF. Their use was safe since associated with lower mortality and morbidity. Our findings confirm the real-world evidence from previous post-hoc analyses of trials, and represent a further call for implementing guideline recommendations.