Abstract Background The Cellular Communication Network Factor-2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-ß and Angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and, in addition, the development of acute and lethal aortic aneurysm induced by Angiotensin II in absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of thoracic aortic aneurysm (TAA). Material and methods 69 patients with TAA and 297 controls were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to CCN2 gene.Multivariable logistic regression models were performed. Results and conclusions While no associations were found between rs6918698 and rs9402373 with TAA development, patients carrying the C allele from rs12526196 polymorphism have a higher probability of suffering TAA compared to patients with TT genotype, independently of other risk factors such as sex, age, hypertension, type of valvulopathy and presence of bicuspid aortic valve (OR = 3.17; 95% CI = 1.30–7.88;P = 0.011). This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulate, for the first time, a protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants, polymorphisms or mutations, in the CCN2 gene that could be predisposing to TAA development. Funding Research funded by ISCIII (PI20/000140, PI18/00694, PI19/00184, PI20/00639); RICORS2040-KIDNEY-DISEASE (RD21/0005/0002, RD21/0005/0017); Sara-Borrell-CD20/00042; Miguel-Servet-CP18/00106; Sociedad Española de Nefrología.