Abstract Background Among patients with heart failure and reduced ejection fraction (HFrEF), angiotensin-converting enzyme inhibitors (ACEI/ARB), β-adrenergic receptor blockers (BB) and aldosterone antagonists (AA) are guideline-directed medical therapy (GDMT) to improve prognosis and well-being. However, low blood pressure (BP) and renal dysfunction are often challenges and barriersof the clinical implementation in real-world. Purpose To investigate whether it is beneficial to apply GDMT in real-world patients with HFrEF despite low blood pressure and renal dysfunction. Methods This study initially included 51060 HF patients from the Swedish Heart Failure Registry. After the exclusion of patients with ejection fraction ≥40% (53.4%), systolic BP>100mmHg (40.0%), eGFR>45ml/min/1.73m2 (3.3.%) and those died during hospitalization (0.3%), 1386 patients were ultimately enrolled in this study. Patients were grouped into five subgroups (ACEI/ARB+BB+AA, ACEI/ARB+BB, ACEI/ARB+AA, ACEI/ARB and BB). Outcome is all cause mortality. Results Among the study patients, 485 (35.0%) were treated with ACEI/ARB+BB+AA, 672 (48.5%) with ACEI/ARB+BB, 41 (3.0%) with ACEI/ARB+AA, 68 (4.9%) with ACEI/ARB and 120 (8.7%) with BB. Patients in ACEI/ARB+BB+AA group were younger (72.9±9.7 vs. 76.1±9.2 vs. 73.9±9.7 vs. 79.5±8.0 vs. 79.3±8.9), with higher BMI (25.4±4.5 vs. 25.5±4.7 vs. 23.7±4.2 vs. 23.4±3.8 vs. 24.7±6.3), more in NYHA I/II (30.8% vs. 33.3% vs. 1.7% vs. 18.9% vs. 24.3%). During the follow-up, all cause mortality was lowest in patients treated with ACEI/ARB+BB+AA (59% vs. 60.4% vs. 75.6% vs. 75% vs. 79.2%). After adjustement for age and gender, when compared with the ACEI/ARB+BB+AA group, the hazard ratio for ACEI/ARB+BB is 1.05 (0.91–1.23), ACEI/ARB+AA 1.16 (0.80–1.68), ACEI/ARB 1.51 (1.11–2.04), and BB 2.36 (1.86–2.98) respectively Conclusions In real-world HFrEF patients with low blood pressure and renal dysfunction, full medication of GDMT is associated with improved long-term survival.