CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is up-regulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer where it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumour margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSEC) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was up-regulated by vascular endothelial growth factor and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 co-localised with the endothelial adhesion molecule/ immunoglobulin superfamily member, vascular cell adhesion molecule-1 (VCAM-1). Functional flow-based adhesion assays with primary human lymphocytes and HSEC demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is up-regulated within the liver during chronic inflammation where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention.