Inhalation of crystalline silica results in pulmonary fibrosis and silicosis. It has been suggested that mast cells play a role in these conditions. How mast cells would influence pathology is unknown. We thus explored mast cell interactions with silica in vitro and in B6.Cg-Kit^W-sh mast cell deficient mice. B6.Cg-Kit^W-sh mice did not develop inflammation or significant collagen deposition following instillation of silica, while C57Bl/6 wild-type mice did have these findings. Given this supporting evidence of a role for mast cells in the development of silicosis, we examined the ability of silica to activate mouse bone marrow derived mast cells (BMMC), including degranulation (-hexosaminidase release), production of reactive oxygen species (ROS) and inflammatory mediators; and the effects of silica on FcRI-dependent activation. Silica did not induce mast cell degranulation. However, TNF-, IL-13 and MCP-1; protease activity, and production of ROS were dose dependently increased following silica exposure and production was enhanced following FcRI stimulation. This mast cell activation was inhibited by anti-inflammatory compounds. As silica mediates some effects in macrophages through scavenger receptors, we first determined that mast cells express scavenger receptors; then explored the involvement of SR-A and MARCO. Silica-induced ROS formation, apoptosis and TNF- production were reduced in BMMC obtained from SR-A, MARCO and SR-A/MARCO KO mice. These findings demonstrate that silica directs mast cell production of inflammatory mediators, in part through scavenger receptors, providing insight into critical events in the pathogenesis and potential therapeutic targets in silicosis.