Silicosis is a chronic lung disease induced by the inhalation of crystalline silica. Exposure of cultured macrophages to crystalline silica leads to cell death, however the mechanism of cell-particle interaction, the fate of particles, and the cause of death are unknown. Time-lapse imaging shows that mouse macrophages avidly bind particles that settle onto the cell surface and cells also extend protrusions to capture distant particles. Using confocal optical sectioning, silica particles were shown to be present within the cytoplasmic volume of live cells. Additionally, electron microscopy and elemental analysis showed silica in internal cellular sections. To further examine the phagocytosis process, the kinetics of particle uptake was quantified using an assay in which cells were exposed to ovalbumin-coated particles, and an anti-ovalbumin antibody was used to distinguish surface-bound from internalized particles. Fc-receptor mediated uptake of antibody-coated silica particles was nearly complete within 5 minutes. In contrast, no ovalbumin-coated particles were internalized at this time. After 30 minutes, 30% of bound silica was internalized and uptake continued slowly thereafter. Ovalbumin-coated latex beads, regardless of surface charge, were internalized at a similarly slow rate. These results demonstrate that macrophages internalize silica and that non-opsonized phagocytosis occurs by a temporally, and possibly mechanistically, distinct pathway from Fc receptor-mediated phagocytosis. Eighty percent of macrophages die within 12h of silica exposure. Neither ovalbumin-coating nor TRITC-labeling has any effect on cell death. Interestingly, antibody-coating dramatically reduces silica toxicity. We hypothesize that the route of particle entry and subsequent phagosome trafficking affects the toxicity of internalized particles.