Inhalation of particulate matter has presented a challenge to human health for thousands of years. The underlying mechanism for biological effect following particle exposure is incompletely understood. We tested the postulate that particle sequestration of cell and mitochondrial iron is a pivotal event mediating oxidant generation and biological effect. In vitro exposure of human bronchial epithelial cells to silica produced a reduction in intracellular iron which resulted in increases in both the importer divalent metal transporter 1 expression and metal uptake. Diminished mitochondrial ⁵⁷Fe concentrations following silica exposure confirmed particle sequestration of cell iron. Pre-incubation of cells with excess ferric ammonium citrate increased cell, nuclear, and mitochondrial metal concentrations and prevented significant iron loss from mitochondria following silica exposure. Cell and mitochondrial oxidant generation increased after silica incubation but pre-treatment with iron diminished this generation of reactive oxygen species. Silica exposure activated MAP kinases (ERK and p38) and altered the expression of transcription factors (nF-kappaB and nrf2), pro-inflammatory cytokines (interleukin-8 and -6), and apoptotic proteins. All these changes in indices of biological effect were either diminished or inhibited by cell pre-treatment with iron. Finally, percentage of neutrophils and total protein concentrations in an animal model instilled with silica was decreased by concurrent exposure to iron. We conclude that an initiating event in the response to particulate matter is a sequestration of cell and mitochondrial iron by endocytosed particle. The resultant oxidative stress and biological response after particle exposure are either diminished or inhibited by increasing the cell iron concentration.