Summary Background In patients with heart failure, interventions to reduce elevated left atrial pressure improve symptoms and reduce the risk of hospital admission. We aimed to assess the safety and potential efficacy of therapeutic left-to-right interatrial shunting in patients with heart failure with reduced ejection fraction. Methods We did this proof-of-principle cohort study at one centre in Canada. Patients (aged ≥18 years) with New York Heart Association (NYHA) class III chronic heart failure with reduced ejection fraction were enrolled under the Canadian special access programme. Shunt implants were done after transseptal catheterisation with transoesophageal echocardiographic guidance under general anaesthesia. Patients had clinical and echocardiography evaluations at baseline and months 1 and 3 after shunt implantation. Findings Between Oct 10, 2013, and March 27, 2015, we enrolled ten patients. The device was successfully implanted in all patients; no device-related or procedural adverse events occurred during follow-up. Transoesophageal echocardiography at 1 month showed that all shunts were patent, with no thrombosis or migration. From baseline to 3 month follow-up, we recorded improvements in NYHA classification (from class III to class II in seven 78% of nine patients, from class III to class I in one 11% patient, and no change in one 11% patient; p=0·0004); quality of life, as assessed by the Duke Activity Status Index (from a mean score of 13 SD 6·2 to 24·8 12·9; p=0·016) and the Kansas City Cardiomyopathy Questionnaire (from a mean score of 44·3 SD 9·8 to 79·1 13·0; p=0·0001); and 6 min walk test distance (from a mean of 244 m SD 112 to 318 m 134; p=0·016). Pulmonary capillary wedge pressure was reduced from a mean of 23 mm Hg (SD 5) at baseline to 17 mm Hg (8) at 3 months (p=0·035), with no changes in right atrial pressure, pulmonary arterial pressure, or pulmonary resistance. No patient was admitted to hospital for worsening heart failure. One (10%) patient was admitted to hospital with gastrointestinal bleeding at month 1; one (10%) patient died after incessant ventricular tachycardia storm, which led to terminal heart failure 2 months post-procedure. Interpretation This first-in-man experience with an implanted left-to-right interatrial shunt demonstrates initial safety and early beneficial clinical and haemodynamic outcomes in patients with heart failure with reduced ejection fraction. Further large-scale randomised studies are warranted. Funding V-Wave.