Exposure to pollutant particles increased respiratory morbidity and mortality. The alveolar macrophages (AMs) are one cell type in the lung directly exposed to particles. Upon contact with particles, AMs are activated and produce reactive oxygen species, but the scope of this oxidative stress response remains poorly defined. In this study, we determined the gene expression profile in human AMs exposed to particles, and sought to characterize the global response of pro- and antioxidant genes. We exposed AMs obtained by bronchoscopy from normal individuals to Chapel Hill particulate matter of 2.5-μm diameter or smaller (PM_2.5; 1 μg/ml) or vehicle for 4 hours (n = 6 independent samples). mRNAs were extracted, amplified, and hybridized to Agilent human 1A microarray. Significant genes were identified by significance analysis of microarrays (false discovery rate, 10%; P ≤ 0.05) and mapped with Gene Ontology in the Database for Annotation, Visualization, and Integrated Discovery. We found 34 and 41 up- and down-regulated genes, respectively; 22 genes (∼30%) were involved in metal binding, and 11 were linked to oxidative stress, including up-regulation of five metallothionein (MT)-1 isoforms. Exogenous MT1 attenuated PM_2.5-induced H₂O₂ release. PM_2.5 premixed with MT1 stimulated less H₂O₂ release. Knockdown of MT1F gene increased PM_2.5-induced H₂O₂ release. PM_2.5 at 1 μg/ml did not increase H₂O₂ release. Mount St. Helens PM_2.5 and acid-extracted Chapel Hill PM_2.5, both poor in metals, did not induce MT1F or H₂O₂ release. Our results show that PM_2.5 induced a gene expression profile prevalent with genes related to metal binding and oxidative stress in human AMs, independent of oxidative stress. Metals associated with PM may play an important role in particle-induced gene changes.