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Treatment of chronic heart failure (CHF) guided by natriuretic peptides has been studied in clinical trials with conflicting results. The aim of this study was to investigate if N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided therapy in symptomatic heart failure patients in primary care would improve clinical outcomes over and above treatment according to guidelines.SIGNAL-HF was a 9 month, randomized, single-blind, parallel group study in patients with CHF in NYHA class II–IV, ejection fraction (EF) <50% and elevated NT-proBNP levels (males >800, females >1000 ng/L). All investigators underwent a pre-study educational programme about current CHF guidelines. A control group managed by non-trained investigators was considered not possible for ethical and practical reasons. Patients were randomized to structured treatment of CHF according to guidelines with or without NT-proBNP monitoring. The choice and dose of therapy for CHF was at the investigator's discretion. The primary outcome variable was the composite endpoint of days alive, days out of hospital, and symptom score from the Kansas City Cardiomyopathy Questionnaire.In all, 252 patients were randomized. The allocation groups were well balanced with regards to age, NT-proBNP, and EF. Treatment doses of beta-blockers and blockers of the renin–angiotensin–aldosterone system were markedly increased towards target doses and to a similar degree in both groups. There were no differences between the groups concerning either the primary endpoint (P = 0.28) or its components [cardiovascular (CV) death, P = 0.93; CV hospitalization, P = 0.88; or symptom score, P = 0.28].NT-proBNP-guided CHF treatment did not result in important improvements in clinical outcomes in patients with CHF in primary care above and beyond what could be achieved by education and structured CHF treatment according to guidelines.