OBJECTIVES: Ambrisentan, a non-sulphonamide endothelin receptor antagonist (ERA) was recently licensed for the treatment of Pulmonary Arterial Hypertension (PAH). The study objective was to estimate the cost-effectiveness of ambrisentan from an Irish Healthcare perspective. METHODS: A discrete event simulation model developed by United BioSource Corporation was used to compare the cost-effectiveness of ambrisentan relative to two other ERAs (bosentan, sitaxentan) over a five year time horizon. The probability of clinical worsening and liver abnormality events were predicted from regression equations derived from the ambrisentan clinical trials data. These regression equations were also used to predict events for the comparator therapies by calibrating them to reproduce treatment effects consistent with those reported in the literature. Costs and utilities were then assigned to these events and were discounted at 3.5%. Costs were obtained from Irish specific and UK sources and were in 2007 prices. Utility values were derived from ambrisentan clinical trials. RESULTS: It was estimated that ambrisentan is cost saving with improved health outcomes compared to both bosentan and sitaxentan; ambrisentan dominated both bosentan (-€195,788/QALY) and sitaxentan (-€138,780/QALY). This result was driven by the higher incidence of liver abnormalities associated with bosentan and sitaxentan compared to ambrisentan. When patients experienced liver abnormalities a proportion of them switched to prostacylin therapy, which was more expensive and associated with lower QALYs than ERA therapy. Probabilistic sensitivity analysis revealed that the likelihood of ambrisentan dominating bosentan and sitaxentan was 86% and 73%, respectively. CONCLUSIONS: Ambrisentan is a cost-effective alternative for the treatment of PAH in Ireland. This is because it results in a lower incidence of liver abnormalities compared to existing ERAs.