Endothelin 1 is implicated in the pathogenesis of systemic sclerosis (SSc), and the endothelin receptor antagonist (ERA) bosentan has shown efficacy in randomized controlled trials (RCTs) in patients with SSc who have digital ulcers. Surprisingly, the novel ERA macitentan has failed to show efficacy in patients with SSc in two phase III RCTs: DUAL-1 (n = 226) and DUAL-2 (n = 216). In both RCTs, the rate at which new active ischaemic digital ulcers developed over 16 weeks was not significantly different in patients who received placebo and those treated with 3 mg macitentan or 10 mg macitentan. In addition, adverse events — such as headache, peripheral oedema and anaemia — were more common in the treatment groups than among patients who received placebo.