Glandular secretion and integrity, local blood flow, salivary secretion, pain perception and neurogenic inflammation can all be controlled by the nervous system. Therefore, the pattern of innervation of labial salivary glands (LSG) was studied in 10 patients with Sjögren's syndrome using neuronal markers: protein gene product 9.5 (PGP 9.5), a cytoplasmic, noncytoskeletal epitope and synaptophysin, a glycoprotein present in presynaptic vesicles. PGP 9.5 immunoreactive nerve fibers were found surrounding the acini, salivary ducts and blood vessels. The rich innervation of LSG was even more evident in immunofluorescence stained sections analyzed using confocal laser scanning imaging. Synaptophysin immunoreactive nerve endings and preterminal varicosities also demarcated the LSG acini. Furthermore, in the small foci, PGP 9.5 and synaptophysin immunoreactive nerve fibers were found amid inflammatory mononuclear cells and in extensive inflammatory areas nerve fibers were found in the peripheral parts of such infiltrates. This suggests a possible neurogenic influence on the local cellular inflammation. When LSG patient samples were compared to unaffected glands from 7 controls, acinar atrophy was found in the areas devoid of a local delivery system of neurogenic trophic stimuli, suggesting this as a possible cause of glandular degeneration. It may become necessary to incorporate this neglected, but existing system into our current view on the local but possibly centrally controlled or influenced pathogenetic mechanisms of Sjögren's syndrome.