Abstract Background Current guidelines recommend that patients with heart failure and a reduced ejection fraction (HFrEF) should receive four foundational treatments, i.e. renin-angiotensin system inhibitor (RASi) or angiotensin-receptor neprilysin inhibitor (ARNi), β-blocker, mineralocorticoid receptor antagonist (MRA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i). There is emerging consensus that simultaneous initiation or rapid sequencing provide greater benefit, enhancing tolerability of these therapies and improving outcomes. However, implementation of a comprehensive approach is limited by common underuse and underdosing, and paucity of data exists on initiating the four pharmacological pillars of HFrEF during hospitalization or at discharge. Aim To investigate the feasibility of a comprehensive pharmacological approach in patients with HFrEF at discharge after an episode of heart failure (HF) hospitalization in a tertiary referral center. Methods In-patients with HFrEF and a first HF hospitalization (2019-2021) were categorized according to the number/type of treatments prescribed at discharge. Prevalence of contraindications and cautions for HFrEF treatments – as defined by current European Society of Cardiology (ESC) guidelines on HF – was as assessed. Logistic regression models were fitted to assess predictors of number of treatments prescribed and risk of re-hospitalization. Results Among 305 patients with HFrEF, 49.2% received at least two current recommended drugs. A β-blocker was prescribed in 93.4% of patients, and a RASi/ARNi in 68.2%. Based on current recommendations, 46.2% of patients could receive four foundational drugs. An MRA was prescribed in 32.5% of patients and 100% of patients did not show contraindications to MRA use. Renal dysfunction was present in 13.1% of patients, while hypotension in 11.8%. Bradycardia and renal dysfunction were associated with lower number of drugs prescribed adjusted OR (95% CI) 0.18 (0.06-0.50), and 0.50 (0.39-0.64), respectively. A higher number of drugs used was associated with no rehospitalization during the 30 days after discharge OR (95% CI) 0.22 (0.10-0.49) per number of pillars increase. Conclusions Based on the presence/absence of contraindications, a quadruple therapy could be implementable in a contemporary cohort of HFrEF in-patients at discharge. Renal dysfunction and bradycardia were the main prevalent conditions limiting the achievement of a more comprehensive therapeutic approach. Use of a higher number of drugs was associated with lower risk of re-hospitalization within 30 days after discharge.