Rationale Exposure to particulate matter (PM) causes lung cancer by mechanisms that are unknown but p53 dysfunction is implicated. Objective We determined whether p53 is required for PM-induced apoptosis in both human and rodent alveolar type II cells. Methods A well- characterized form of urban PM was used to determine whether it induces mitochondrial dysfunction (mitochondrial membrane potential change [m] and caspase 9 activation), p53 protein and mRNA expression, and apoptosis (DNA fragmentation and annexin V staining)in vitro using A549 cells as well as primary isolated human and rat alveolar type II cells. The role of p53 was assessed using inhibitors of p53-dependent transcription, pifithrin-, and a genetic approach (overexpressing E6 or dominant/negative p53). The in vivo effects of PM in mice causing p53 expression and apoptosis were assessed 72 h after a single PM intratracheal instillation. Measurements and Main Results PM-induced apoptosis in A549 cells was characterized by increased p53 mRNA and protein expression, mitochondrial translocation of Bax and p53, a reduction in m, and caspase-9 activation and these effects were blocked by inhibiting p53-dependent transcription. Similar findings were noted in primary isolated human and rat alveolar type II cells. A549-° cells that are incapable of mitochondrial ROS production were protected against PM- induced m, p53 expression and apoptosis. In mice, PM induced p53 expression and apoptosis at the broncho-alveolar duct junctions. Conclusions These data suggest a novel interaction between p53 and the mitochondria in mediating PM-induced apoptosis that is relevant to the pathogenesis of lung cancer from air pollution.