The inflammatory response following particle inhalation is described as a key event in the development of lung diseases, e.g. fibrosis and cancer. The essential role of alveolar macrophages (AM) in the pathogenicity of particles through their functions in lung clearance and mediation of inflammation is well known. However, the molecular mechanisms and direct consequences of particle uptake are still unclear. Inhibition of different classical phagocytosis receptors by flow cytometry shows a reduction of the dose-dependent quartz particle (DQ12) uptake in the rat AM cell line NR8383. Thereby the strongest inhibitory effect was observed by blocking the FcII-receptor (FcII-R). Fluorescence immunocytochemistry, demonstrating FcII-R clustering at particle binding sites as well as transmission electron microscopy, visualizing zippering-mechanism-like morphological changes, confirmed the role of the FcII-R in DQ12 phagocytosis. FcII-R participation in DQ12 uptake was further strengthened by the quartz-induced activation of the Scr-kinase Lyn, the phospho-tyrosine-kinases Syk (Spleen-Tyrosine-kinase) and PI3K (Phosphatidylinositol3-kinase) as shown by Western blotting. Activation of the small GTPases Rac1 and Cdc42, shown by immunoprecipitation, as well as inhibition of tyrosine-kinases, GTPases, or Rac1 provided further support for the role of the FcII-R. Consistent with the uptake results, FcII-R activation with its specific ligand caused a similar generation of reactive oxygen species (ROS) and TNF- release as observed after treatment with DQ12. In conclusion, our results indicate a major role of FcII-R and its downstream signaling cascade in the phagocytosis of quartz particles in AM as well as in the associated generation and release of inflammatory mediators.