Abstract Background Marfan Syndrome (MFS) is a rare multisystemic genetic disease caused by mutations in the Fibrillin 1 (FBN1) gene. Aortic root aneurysm, potentially evolving to dissection and rupture, is the most important clinical complication. Beta blockers (BB) and Angiotensin II receptor blockers (ARB), these latter exerting an anti-TGFbeta1 effect, are current cornerstones of medical therapy in patients diagnosed with MFS and presenting aortic root aneurysm. The study aimed at comparing the effect of single drug (nebivolol and losartan) vs. the combination of both (losartan + nebivolol) in limiting the progression of the growth of the aortic root diameter (ARD) in FBN1 genotyped patients with aortic root aneurysm (z-score>2), who had not undergone prior aortic surgery. Methods We designed a controlled, open-label, single-blinded, 1:1:1 randomized, phase III single-centre study [NCT00683124]. Calculated sample size was 291 (power 90%, type I error 5%, 20% attrition, expected dropout 20%). ARD data collection was performed with annual 2D-transthoracic echocardiograms for four years. ARDs were measured with 2D-transthoracic echocardiogram as absolute values, aortic root ratio (ARR), and z-score. The primary endpoint was the modification of ARD z-score at 48 months. The analysis of the primary endpoint aimed at showing differences of ARD z-score comparing: – The combined treatment arm (group A). – The group aggregating both single treatment arms (group B). – The nebivolol arm (group C). – The losartan arm (group D). Results We enrolled 262 patients (126 adults, aged 17–55, and 136 children, aged 1–16); 236/262 (22 dropout; 4 lost at follow-up) completed the planned follow-up: 81 in the group A, 79 in the BB in the group C and 76 in the group D. No patient developed acute aortic dissection. Both drugs administered either individually or in combination were well tolerated without evidence of side effects. At 48 months, the ARD Z-score decreased from baseline to end-follow-up in all treatment arms. The decrease was significantly higher in the combined treatment arm (A) than in the single treatment aggregated arm (group B) with a difference in ARD z-score change of 0.17 (p=0.009) in the combined arm (A). Similarly, the decrease of z-score was inferior in the nebivolol arm and in the losartan arm than in the combined arm (by 0.16, p=0.032, and by 0.18, p=0.019, respectively). After Bonferroni correction for these post-hoc comparisons only the decrease of z-score in the losartan arm remained significantly inferior (p<0.025). Conclusions This study shows that the current cornerstones of medical therapy in MFS (ARB and BB) are effective in limiting the progression of the growth of the aortic root diameter: their combination exploits a synergistic effect. The combined administration of BB and ARB in patients with aortic root aneurysm is a sustainable, well tolerated treatment that effectively limits the rate of progression of aortic root dilation. Acknowledgement/Funding The financial support of Telethon, Italy (Grant no. GGP08238) is gratefully acknowledged.The drugs are a gift of Menarini and MSD