Synaptophysin is a protein involved in neurotransmitter exocytosis and is a neuroendocrine marker.We studied synaptophysin immunohistochemical expression in 35 human liver specimens (normal and different pathological conditions) , in rat models of galactosamine hepatitis and carbon tetrachloride-induced cirrhosis , and in freshly isolated rat stellate cells. Synaptophysin reactivity was present in perisinusoidal stellate cells in both human and rat normal liver biopsies. The number of synaptophysin-reactive perisinusoidal cells increased in pathological conditions. Double staining for ␣-smooth muscle actin and synaptophysin , detected by confocal laser scanning microscopy , unequivocally demonstrated colocalization of both markers in lobular stellate cells. In addition , freshly isolated rat stellate cells expressed synaptophysin mRNA (detected by polymerase chain reaction) and protein. Finally , electron microscopy showed the presence of small electron translucent vesicles , comparable to the synaptophysin-reactive synaptic vesicles in neurons , in stellate cell projections. We conclude that synaptophysin is a novel marker for quiescent as well as activated hepatic stellate cells. Together with the stellate cell's expression of neural cell adhesion molecule , glial fibrillary acidic protein , and nestin , this finding raises questions about its embryonic origin and its differentiation. In addition , the presence of synaptic vesicles in stellate cell processes suggests a hitherto unknown mechanism of interaction with neighboring cells. (Am J Pathol 1999, 155:1831-1839)