Background In this multi-centre, randomised, placebo-controlled pilot trial, we investigated the clinical and haemodynamic effects of the endothelin-receptor blocker Bosentan in patients with heart failure, preserved ejection fraction and pulmonary hypertension (PH-HFpEF).Materials and Methods Eligible patients received either 12 weeks of Bosentan therapy, or a placebo drug. Patients were thereafter followed for a further period of 12 weeks without the study medication. At three points during the study (study Commencement, Week 12 and Week 24), a six-minute walk test (6MWT), echocardiographic and laboratory assessments were performed, as well as a quality of life survey. Right heart catheterisation (RHC) was undertaken at commencement only. The study was aborted early, after an interim analysis favoured the placebo.Results Six-minute walk distance (6MWD) did not change in the Bosentan group (309.7 +/- 96.3m (Commencement), 317.0 +/- 126.1m (Week 12), 307.0 +/- 84.4m (Week 24); p = 0.86), but almost reached statistical significance in the placebo group from 328.8 +/- 79.6m, to 361.6 +/- 98.2m and 384.0 +/- 74.9m (Week 24); p = 0.075. In the placebo group, estimated systolic pulmonary artery pressure (measured via echocardiography) significantly decreased (from 62.3 +/- 16.7 mmHg [Commencement], 45.3 +/- 13.9 mmHg [Week 12], to 44.6 +/- 14.5 mmHg [Week 24]; p = 0.014) as did right atrial pressure (13.1 +/- 5.3 [Commencement], 10.0 +/- 3.8 [Week 12], to 9.4 +/- 3.2 [Week 24]; p = 0.046).Conclusion Despite this study's limited sample size and premature cessation, it nevertheless suggests that endothelin receptor blockade in patients with PH-HFpEF may have no beneficial effects and could even be detrimental in comparison to a placebo.