In pulmonary arterial hypertension (PAH), upfront combination therapy is associated with better clinical outcomes and a greater reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) than monotherapy. NT-proBNP levels reflect right ventricular (RV) wall stress, which increases when the right ventricle dilates. This study explored the impact of upfront combination therapy on RV volumes compared with monotherapy in PAH patients.This retrospective study involved 80 incident PAH patients (New York Heart Association class II and III) who were treated with upfront combination therapy (n=35) (i.e. endothelin receptor antagonists (ERAs) plus phosphodiesterase-5-inhibitors (PDE5Is)) or monotherapy (n=45) (i.e. either ERAs or PDE5Is). All patients underwent right-sided heart catheterisation and cardiac magnetic resonance imaging at baseline and after 1-year follow-up.Combination therapy resulted in more significant reductions in pulmonary vascular resistance and pulmonary pressures than monotherapy. NT-proBNP was decreased by ∼77% in the combination therapy group compared with a ∼51% reduction after monotherapy (p<0.001). RV volumes and calculated RV wall stress improved after combination therapy (both p<0.001) but remained unchanged after monotherapy (both p=NS). RV ejection fraction improved more in the combination therapy group than in the monotherapy group (p<0.001).In PAH patients, upfront combination therapy was associated with improved RV volumes.