Mast cells are involved in inflammatory processes and in allergic reactions where immunologic stimulation leads to degranulation and generation of numerous cytokines and inflammatory mediators. Mast cells have been proposed as an immune gate to the brain, as well as sensors of environmental and emotional stress, and are likely involved in neuropathologic processes such as multiple sclerosis. Among mast cell products, the protease tryptase could be associated with neurodegenerative processes through the activation of specific receptors (PARs) expressed in the brain, while interleukin (IL)-6 likely causes neurodegeneration and exacerbates dysfunction induced by other cytokines; or it could have a protective effect against demyelinisation. In this report we show that quercetin, a natural compound able to act as an inhibitor of mast cell secretion, causes a decrease in the release of tryptase and IL-6 and the down-regulation of histidine decarboxylase (HDC) mRNA from human mast cell (HMC)-1 cells. As quercetin dramatically inhibits mast cell tryptase and IL-6 release and HDC mRNA transcription by HMC-1 cell line, these results nominate quercetin as a therapeutical compound in association with other therapeutical molecules for neurological diseases mediated by mast cell degranulation.