Background: Raynaud’s phenomenon (RP) is a digital ischemia caused by vasoconstriction in the digital blood vessels. Triggers of RP include cold and stress. Medical therapy for RP is unsatisfactory, with many patients not responding to treatment. Here we investigated the safety, efficacy and pharmacokinetics of riociguat, a soluble guanylate cyclase stimulator, in patients with RP. Methods: Patients who had primary RP or secondary RP associated with systemic sclerosis (SSc), and a symptom duration of ≥1 year, were randomized to receive a single oral dose of riociguat 2 mg or placebo. Digital blood flow (DBF) in the right index finger was determined by Laser Speckle Contrast Analysis at room temperature (RT) and after 5 minutes of cold water exposure (CWE), both at baseline and 2 hours after study drug administration. Results: In the patients valid for evaluation (n=20), treatment with riociguat led to an increase in DBF versus baseline of 40.6% at RT and 15.1% after CWE. Based on predefined criteria, patients were considered responders if the placebo-corrected DBF after CWE increased by ≥10% versus baseline at 2 hours after drug intake. This was the case in 12/20 (60%) patients. The highest response rates were seen in patients with primary RP and limited cutaneous SSc, whereas patients with RP associated with diffuse cutaneous SSc responded less well. In responders, riociguat led to an increase in DBF versus baseline of 135.7% at RT and 38.9% after CWE. Riociguat Cmax (SD) 2 hours after drug intake was 76 (1.5) μg/ml, which is in the range previously seen in healthy volunteers and patients with pulmonary hypertension. Comparable Cmax values were observed in responders (81 [1.5] μg/ml) and non-responders (71 [1.6] μg/ml). AEs were reported in 5 patients receiving riociguat (headache, n=4; dyspepsia, n=1) and 1 patient receiving placebo (malaise). No serious AEs were reported. Conclusions: In this small pilot study, riociguat was well tolerated in patients with primary and secondary RP, and improved DBF versus placebo in 60% of patients after cold exposure.