BACKGROUND Subcutaneous treprostinil has dose-dependent beneficial effects in patients with severe pulmonary arterial hypertension, but adverse effects like infusion site pain can lead to treatment discontinuation. OBJECTIVES The objective of this study was to evaluate safety, tolerability and clinical effects of a rapid up-titration dosing regimen of subcutaneous treprostinil using proactive infusion site pain management. METHODS Effects of rapid up-titration dosing regimen on tolerability and clinical parameters were evaluated in this 16-week, open-label multi-centre study. RESULTS Thirty-nine patients with idiopathic or heritable pulmonary arterial hypertension on stable treatment with oral pulmonary arterial hypertension-approved drugs (90% on dual combination therapy) were included. Patients achieved a median treprostinil dosage of 35.7 ng/kg/min after 16 weeks. A good overall safety profile was demonstrated with 3 patients (8%) withdrawing due to infusion site pain, which occurred in 97% of patients. After 16 weeks, median 6-min walking distance, cardiac index, pulmonary vascular resistance, and tricuspid annular plane systolic excursion improved. CONCLUSIONS Rapid up-titration of subcutaneous treprostinil was well tolerated, achieving a clinically effective dose associated with improvement of exercise capacity and haemodynamics after 16 weeks. A rapid dose titration regimen and proactive infusion site pain management may improve the handling of this therapy and contribute to better treatment outcome.