Tumor necrosis factor alpha (TNFalpha) plays an important role in the pathogenesis of silicosis and other chronic inflammatory lung diseases. The present study investigates the role nuclear transcription factor kappaB (NF-kappaB) and oxygen free radicals in silica-induced TNFalpha production in primary alveolar macrophages and RAW 264.7 cells. Using electrophoretic mobility shift assay (EMSA) and enzyme-linked immunoadsorbent assay (ELISA), we have demonstrated that silica can induce NF-kappaB activation and TNFalpha expression in a dose-dependent manner. Transient transfection assays with a plasmid construct containing NF-kappaB binding sites linked to a reporter gene further show that silica is able to induce the transcriptional activation of NF-kappaB-dependent gene. Inhibition of NF-kappaB activation by SN50, a specific NF-kappaB blocker, abolishes silica-induced TNFalpha production. Pretreatment of the cells with catalase (H2O2 scavenger) or deferoxamine (*OH scavenger) effectively inhibits NF-kappaB and TNFalpha activation, whereas superoxide dismutase (O2 scavenger) has an opposite effect. These results indicate that silica-mediated free radical generation and NF-kappaB activation play important roles in silica-induced TNFalpha gene expression.