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BACKGROUND: Monotherapy and sequential combination therapy have been widely used in the treatment of pulmonary arterial hypertension (PAH). There is limited evidence for initial combination therapy in patients with PAH, particularly those with World Health Organization (WHO) functional class III or IV. METHODS: Twenty-seven consecutive treatment-naive PAH subjects with WHO functional class III or IV PAH were randomized into 3 groups with a 1:1:1 ratio: a combination therapy group with 125 mg of bosentan twice daily plus 10 µg of iloprost 4-6 times/d; a bosentan monotherapy group with 125 mg of bosentan twice daily; and a iloprost monotherapy group with 10 µg of iloprost 4-6 times/d. Clinical and hemodynamic data were collected at baseline, 6 weeks, and 3 months. The primary end point was the change in the 6-min walk distance (6MWD) from baseline values. RESULTS: At baseline, there were no differences in demographics, WHO classification, hemodynamics, classification of PAH, or 6MWD among the 3 groups. The 6MWD significantly improved in the combination therapy group compared with the bosentan monotherapy and iloprost monotherapy groups at week 6 (P = .001) and after 3 months (P < .001), respectively. Secondary end points significantly improved in the combination therapy group for mean pulmonary artery pressure, cardiac index, and WHO functional classification after 3 months of treatment and for N-terminal pro-brain natriuretic peptide, Minnesota Living with Heart Failure questionnaire scores, and PaO2 after 6 weeks and 3 months of treatment, compared with the monotherapy groups. CONCLUSIONS: Initial combination therapy in treatment-naive PAH subjects with WHO functional class III or IV can significantly improve 6MWD, hemodynamics, and quality of life compared with monotherapy. Further studies with large samples and placebo controls are required to assess the tolerability and efficacy of initial combination therapy in patients with PAH. (ClinicalTrials.gov registration NCT01712997). [ABSTRACT FROM AUTHOR]