We assessed the safety, tolerability and preliminary efficacy of riociguat, a soluble guanylate cyclase stimulator, in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD).In this open-label, uncontrolled pilot trial, patients received oral riociguat (1.0-2.5 mg t.i.d.) for 12 weeks (n=22), followed by an ongoing long-term extension (interim analysis at 12 months) in those eligible (n=15). Primary endpoints were safety and tolerability. Secondary endpoints included haemodynamic changes and 6-minute walk distance (6MWD).Overall, 104 adverse events were reported, of which 25 were serious; eight of the latter were considered drug-related. After 12 weeks of therapy, mean cardiac output increased (4.4±1.5 L·min(-1) to 5.5±1.8 L·min(-1)), pulmonary vascular resistance (PVR) decreased (648±207 dyn.s.cm(-5) to 528±181 dyn.s.cm(-5)) and mean pulmonary artery pressure (PAPm) remained unchanged compared with baseline. Arterial oxygen saturation decreased but mixed-venous oxygen saturation slightly increased. The 6MWD increased from 325±96 m at baseline to 351±111 m after 12 weeks.Riociguat was well tolerated by most patients and improved cardiac output and PVR, but not PAPm. Further studies are necessary to evaluate the safety and efficacy of riociguat in patients with PH-ILD.