Background: Heart failure (HF) affects around 500,000 people in the UK. HF medications are frequently underprescribed and B-type natriuretic peptide (BNP)-guided therapy may help to optimise treatment. Objective: To evaluate the clinical effectiveness and cost-effectiveness of BNP-guided therapy compared with symptom-guided therapy in HF patients. Design: Systematic review, cohort study and cost-effectiveness model. Setting: A literature review and usual care in the NHS. Participants: (a) HF patients in randomised controlled trials (RCTs) of BNP-guided therapy; and (b) patients having usual care for HF in the NHS. Interventions: Systematic review: BNP-guided therapy or symptom-guided therapy in primary or secondary care. Cohort study: BNP monitored (≥ 6 months’ follow-up and three or more BNP tests and two or more tests per year), BNP tested (≥ 1 tests but not BNP monitored) or never tested. Cost-effectiveness model: BNP-guided therapy in specialist clinics. Main outcome measures: Mortality, hospital admission (all cause and HF related) and adverse events; and quality-adjusted life-years (QALYs) for the cost-effectiveness model. Data sources: Systematic review: Individual participant or aggregate data from eligible RCTs. Cohort study: The Clinical Practice Research Datalink, Hospital Episode Statistics and National Heart Failure Audit (NHFA). Review methods: A systematic literature search (five databases, trial registries, grey literature and reference lists of publications) for published and unpublished RCTs. Results: Five RCTs contributed individual participant data (IPD) and eight RCTs contributed aggregate data (1536 participants were randomised to BNP-guided therapy and 1538 participants were randomised to symptom-guided therapy). For all-cause mortality, the hazard ratio (HR) for BNP-guided therapy was 0.87 [95% confidence interval (CI) 0.73 to 1.04]. Patients who were aged