Our current understanding of the pathophysiology of pulmonary vascular disease is incomplete, since information about alterations of the pulmonary vasculature in pulmonary arterial hypertension (PAH) is primarily provided by autopsy or tissue specimens. The aim of this study was to compare the distal pulmonary vasculature of <2 mm in diameter in Systemic Sclerosis (SSc) patients with (n = 17) and without (n = 5) associated PAH using Optical Coherence Tomography during Right Heart catheterization. SSc-PAH patients showed significant thickening of Intima Media Thickening Area compared to patients without PAH (27 +/- 5.8% vs. 21 +/- 1.4%, p = 0.024). A good haemodynamic response to previous targeted PAH treatment was associated with a significantly greater number of small pulmonary artery side branches <300 μm per cm vessel (3.8 +/- 1.1 vs. 1.8 +/- 1.1; p = 0.010) and not associated with Intima Media thickening Area (26 +/- 5.4% vs. 28 +/- 6.7%; p = 0.6). Unexpected evidence of pulmonary artery thrombus formation was found in 19% of SSc-PAH patients. This is the first in-vivo study demonstrating a direct link between a structural abnormality of pulmonary arteries and a response to targeted treatment in PAH. Intravascular imaging may identify subgroups that may benefit from anticoagulation.