Aims Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real‐world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE‐HF study started to prospectively investigate the use, sequencing, and titration of guideline‐directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. Methods and results TITRATE‐HF is an ongoing long‐term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range IQR 63–78), 29% were female, and median ejection fraction was 35% (IQR 25–40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non‐use in HFrEF patients was related to side‐effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. Conclusion This first analysis of the TITRATE‐HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management. Guideline‐directed medical therapy (GDMT) use and dosing in all chronic and worsening heart failure with reduced ejection fraction patients. (A) Percentage of patients using GDMT, stratified by drug class. (B) Reasons for GDMT non‐use. (C) Percentage of target dose for each drug class, stratified by <50% of target dose, 50% to 100% of target dose, and ≥100% of target dose. ARNI, angiotensin receptor–neprilysin inhibitor; BB, beta‐blocker; MRA, mineralocorticoid receptor antagonist; RASi, renin–angiotensin system inhibitor; SGLT2i, sodium–glucose cotransporter 2 inhibitor; TD, target dose.