Rationale: Alveolar macrophages are inflammatory cells that may contribute to the pathogenesis of idiopathic pulmonary fibrosis, which is characterized by excessive alveolar aggregation of cells and extracellular matrix proteins. Objectives: To identify potential molecular mechanisms of idiopathic pulmonary fibrosis. Methods: To examine large-scale gene expression, messenger RNA isolated from alveolar macrophages and peripheral blood mononuclear cells from subjects with idiopathic pulmonary fibrosis and normal volunteers was hybridized to cDNA filters. Measurements and Main Results: We showed that in idiopathic pulmonary fibrosis there is global downregulation of gene expression in alveolar macrophages, but not in blood monocytes. Nuclear run-on and pulse-chase studies showed that alveolar macrophages had significantly reduced transcription (P<0.01). No significant difference in RNA degradation was found between idiopathic pulmonary fibrosis subjects and normal volunteers. Western blot analyses revealed that concentrations of transcription factor II-H (TFII-H), a general transcription factor, were significantly lower in alveolar macrophages from subjects with idiopathic pulmonary fibrosis than in those from normal volunteers (P=0.012). Conclusions: Impaired transcription in idiopathic pulmonary fibrosis is associated with decreased concentrations of transcription factor II-H in alveolar macrophages and may alter the intra-alveolar milieu in idiopathic pulmonary fibrosis.