OBJECTIVES: To evaluate health outcomes and costs of initiation with endothelin receptor antagonists [ERA] monotherapy (ambrisentan or bosentan) followed by sequential combination with phosphodiesterase-5 inhibitors [PDE-5] and prostanoids in the treatment of pulmonary arterial hypertension in Spain. METHODS: A Markov model was developed based on New York Hearth Association functional classes. Transition probabilities [TP] for ERA initiation were gathered from the pivotal clinical trials. Outcomes were measured in quality-adjusted life years [QALY]. A panel of 3 independent experts reached a consensus on patient management based on clinical practice. Patients initiated treatment with either ambrisentan or bosentan, and revised treatment every 12 weeks based on their health status and previous medication records. A National Health System perspective was adopted. Pharmacological costs and costs associated with very frequent adverse events [AE] (i.e. edema and hepatic abnormalities) were included. Following a first-order Monte Carlo simulation approach, 1,000 hypothetical patients were observed in a temporal horizon of 60 weeks. This simulation was repeated 1,000 times. RESULTS: Average (per-patient and year) pharmacological costs [95% CI] were €35,550 [€34,944-€36,196] and €40,224 [€39,264-€41,212] for initiation with ambrisentan and bosentan, respectively. Average costs associated with AE management were €117 [€110-€124] and €171 [€160-€182], respectively. No clinically relevant differences in average QALY were found: 0.6853 [0.6836-0.6870] and 0.6903 [0.6885-0.6921], respectively. This agrees with published meta-analyses and a priori expert judgment. Initiation with ambrisentan would bring about cost savings of €4,727 [€3,903-€5,620]. From a cost-minimization perspective, if the same TP were considered for both initiation alternatives, initiation with ambrisentan would provide cost savings of €4,952 [€4,898-€5,007] (using ambrisentan’s TP) and €4,770 [€4,718-€4,819] (using bosentan’s TP). CONCLUSIONS: Initiation with ambrisentan monotherapy followed by sequential combination with PDE-5 and prostanoids yields comparable outcomes at lower costs than initiation with bosentan. These results might be considered in hospital pharmacy budget allocation decision making.