Objectives The comparative efficacy between riociguat and selexipag in patients with pulmonary arterial hypertension (PAH) has never been described in literature. Our aim was to prepare indirect treatment comparison (ITC) to evaluate the cost-effectiveness of riociguat in Czechia. Methods A systematic literature review identified two relevant trials with comparable endpoints to inform a Bucher ITC of relative and absolute effects. Given the comparable efficacy of riociguat and selexipag, a cost-minimization analysis (CMA) was conducted. Results A Bucher ITC provided evidence for the comparable relative efficacy of riociguat defined as the odds of unimproved functional class III 0.761 (95% CI 0.372 to 1.558; p = 0.455) compared to selexipag and a comparable absolute efficacy defined as a difference in the 6-minute walking distance of 10.560 meters (95% CI -10.692 to 31.812; p = 0.330). The CMA identified riociguat as the cost-saving therapy. Conclusions Switching to riociguat represents the cost-saving therapy for PAH patients who were inadequately compensated with the PDE5i+ERA therapy. Consequently, riociguat has been introduced to the list of reimbursed medicines in Czechia from October 2021. Based on two global trials, we prepared the first indirect treatment comparison followed with CMA of these therapies that may improve future decision-making for PAH indications.