The identification and specific functions of Kupffer cells (KCs), a liver resident macrophage subpopulation, are still unclear. We compared KCs with peritoneal macrophages using cDNA microarray analysis and found that these cells share some antigens with endothelial cells. KCs highly express VCAM-1 and VEGF receptors (VEGF-Rs) at transcriptional and protein levels. VCAM-1 mediates the functional binding of KCs with lymphocytes and induces KC activation. Among the VEGF receptors, VEGF-R2 and VEGF-R3 were expressed on the KCs, while VEGF-R1 was expressed on other tissue macrophage subsets. VEGF120, a ligand of both VEGF-R1 and VEGF-R2, transduced strong survival and chemotactic signals through the KCs, when compared to PIGF, a VEGF-R1 ligand, indicating that VEGF-R2 plays significant roles in regulating KC activities. Expression of the VEGF-Rs was regulated by TLR4 signalling. These results suggest that the function of KCs is partly regulated by the common antigens shared with endothelial cells.