OBJECTIVES: To examine evidence on efficacy and safety of oral drugs for pulmonary arterial hypertension (PAH). Analyze their utilization and their cost. To propose a treatment protocol based on efficacy, safety and efficiency. Calculate the estimated budget impact after its implementation. METHODS: A search was conducted in MEDLINE, EMBASE and Cochrane Database. Systematic reviews and meta-analysis of bosentan, ambrisentan, sildenafil or tadalafil in PAH (functional class II/III) were included. Their utilization was analyzed retrospectively in patients with primary or associated with connective tissue diseases pulmonary hypertension that started treatment during 2008 to 2010. The annual cost per patient for each alternative was calculated (standard dosage). A treatment protocol was developed, based on efficacy, safety, and efficiency. The incremental cost for each drug, and the potential savings if all patients start their treatment with the most cost-effective were calculated. RESULTS: No evidence was found to support the superiority of any treatment over another, in terms of efficacy and/or safety. Seventeen patients started treatment during the study period (47% bosentan, 41.2% sildenafil, 11.8% ambrisentan). Estimated annual cost per patient: 30,987.07, 26,861.93, 7,807.74 and 6,865.65 €, for bosentan, ambrisentan, sildenafil and tadalafil, respectively. In absence of significant differences in efficacy or safety, the treatment protocol was based on efficiency (sildenafil> tadalafil> ambrisentan> bosentan). Incremental cost (compared to sildenafil): 24,121.42, 19,996.28 and €942.09 for bosentan, ambrisentan and tadalafil, respectively. Estimated potential savings with implementation of protocol: 77,654.64 €/ year. CONCLUSIONS: No evidence supports the superiority of any treatment over another, so they could be considered equivalent therapeutic alternatives. Bosentan is most widely used drug in naïve patients. The cost associated with bosentan/ambrisentan is markedly greater to sildenafil/tadalafil. Establishing a protocol that prioritizes sildenafil/tadalafil use would help to more efficient management of resources.