Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Treatment with losartan, an angiotensin-II receptor-1 blocker, may reduce aortic dilatation rate in Marfan patients. In this multicentre, open-label, randomized controlled trial with blinded assessments, we compared losartan treatment with no additional treatment in operated and unoperated adults with Marfan syndrome. The primary endpoint was aortic dilatation rate at any predefined aortic level after 3 years of follow-up, as determined by magnetic resonance imaging. A total of 233 participants (47% female) underwent randomization to either losartan (n = 116) or no additional treatment (n = 117). Aortic root dilatation rate after 3.1 ± 0.4 years of follow-up was significantly lower in the losartan group than in controls (0.77 ± 1.36 vs. 1.35 ± 1.55 mm, P = 0.014). Aortic dilatation rate in the trajectory beyond the aortic root was not significantly reduced by losartan. In patients with prior aortic root replacement, aortic arch dilatation rate was significantly lower in the losartan group when compared with the control group (0.50 ± 1.26 vs. 1.01 ± 1.31 mm, P = 0.033). No significant differences in separate clinical endpoints or the composite endpoint (aortic dissection, elective aortic surgery, cardiovascular death) between the groups could be demonstrated. In adult Marfan patients, losartan treatment reduces aortic root dilatation rate. After aortic root replacement, losartan treatment reduces dilatation rate of the aortic arch.