Abstract OBJECTIVES Existing surgical sealants fail to combine design requirements, such as sealing performance, on-demand activation and biocompatibility. The aim of this study was to compare the effectiveness and safety of the SETALIUM™ Vascular Sealant (SVS), a novel, on-demand activatable sealant, with the commercial sealant, BioGlue®, for the repair of vascular defects. METHODS In an in vivo porcine model, the use of SVS was compared with BioGlue, for sealing 2-mm defects of the carotid artery and jugular vein. Animals were followed for 7 days and 5 weeks (each time point and per experimental group, n = 4), respectively. The degree of stenosis and flow velocity was determined, and the local tissue response was evaluated. RESULTS In vivo incision closure succeeded in all cases, and SVS was superior in clinical usability, enabled by its on-demand activation. Unlike BioGlue, SVS use did not induce stenosis and was associated with physiological blood flow in all cases. Moreover, closure with SVS was associated with a low inflammatory reaction and no thrombus formation or intima proliferation, in contrast to BioGlue. CONCLUSIONS SVS demonstrated effective and rapid sealing of 2-mm vascular defects, with favourable biocompatibility compared to BioGlue. Thus, SVS seems to be an effective and safe vascular sealant.