PURPOSE: The purpose of the study is to describe the trajectories of oral medication prescriptions in patients with heart failure with reduced ejection fraction (HFrEF) over 3 years after discharge from hospitalization for heart failure. We then evaluated the adherence of these prescriptions to the European Society of Cardiology (ESC) guideline-recommended medications and identified patient characteristics associated with nonadherence. METHODS: We used data from the EPICAL2 cohort study. HFrEF patients who had completed prescriptions at discharge and at 6-month follow-up were included and followed for 36 months. The following medication agents were considered adherent to guidelines: renin-angiotensin system (RAS) blockers [angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin-receptor blocker (ARB)] plus a β-blocker (BB) or RAS blocker plus BB plus mineralocorticoid receptor antagonists (MRAs). The evolution of drug prescriptions and the adherence to ESC guidelines were assessed by using sequence analysis and clustering approaches. Patient characteristics associated with nonadherence were identified by logistic regression analyses. RESULTS: A typology of four therapeutic clusters was obtained, among which two clusters were adherent to recommendations and two were not. The adherent clusters consisted of bitherapy (RAS blockers-BB) and tritherapy (RAS blockers-BB-MRA) for about 64% of patients and remain stable over time. The nonadherent clusters consisted of nonprescription of BB for about 22% of patients or nonprescription of RAS blocker for about 14%. The main reason for nonprescription of BB was a concomitant obstructive airway disease (asthma or COPD) but was a concomitant chronic kidney disease for nonprescription of RAS blocker. CONCLUSION: Adherence to guideline-recommended medications while being hospitalized is of great importance because prescriptions are quite stable over time after discharge. HFrEF patients are most often older, with various comorbidities, such as chronic kidney disease or asthma/COPD, which importantly limit physicians' ability to prescribe recommended drugs, leading to suboptimal adherence to guidelines.