Aim Sepsis is a systemic inflammatory response syndrome resulting from a microbial infection. Transforming growth factor β‐induced protein (TGFBIp) is an extracellular matrix protein expressed by human endothelial cells and platelets that induces sepsis through interaction with integrin αvβ5. The aim of this study was to investigate the role of TGFBIp in vascular permeability and the underlying mechanisms using TGFBIp‐neutralizing antibody. Methods Mice were subjected to caecal ligation and puncture (CLP) with or without neutralizing anti‐TGFBIp antibody (300 μg kg−1, intravenously). Wild‐type or integrin β5‐null mice received TGFBIp (0.1 mg kg−1, intravenously) or were subjected to CLP. Human umbilical vein endothelial cells were exposed to lipopolysaccharide (100 ng mL−1) with or without neutralizing anti‐TGFBIp antibody (50 μg mL−1). Results Administration of neutralizing anti‐TGFBIp antibody in mice attenuated CLP‐induced secretion of TGFBIp, leucocyte migration and vascular permeability and reduced septic mortality. Injected TGFBIp did not enhance vascular barrier permeability or leucocyte migration in β5‐null mice. Finally, neutralizing anti‐TGFBIp antibody inhibited the specific interactions between TGFBIp and its receptor, integrin αvβ5. Conclusion Our findings demonstrate that treatment with a TGFBIp‐neutralizing antibody can ameliorate the deleterious effects of sepsis.