Air pollution is associated with significant adverse health effects, including increased cardiovascular morbidity and mortality. Exposure to particulate matter with an aerodynamic diameter of <2.5 µm (PM_2.5) increases ischemic cardiovascular events and promotes atherosclerosis. Moreover, there is increasing evidence that the smallest pollutant particles pose the greatest danger because of their high content of organic chemicals and prooxidative potential. To test this hypothesis, we compared the proatherogenic effects of ambient particles of <0.18 µm (ultrafine particles) with particles of <2.5 µm in genetically susceptible (apolipoprotein E–deficient) mice. These animals were exposed to concentrated ultrafine particles, concentrated particles of <2.5 µm, or filtered air in a mobile animal facility close to a Los Angeles freeway. Ultrafine particle–exposed mice exhibited significantly larger early atherosclerotic lesions than mice exposed to PM_2.5 or filtered air. Exposure to ultrafine particles also resulted in an inhibition of the antiinflammatory capacity of plasma high-density lipoprotein and greater systemic oxidative stress as evidenced by a significant increase in hepatic malondialdehyde levels and upregulation of Nrf2-regulated antioxidant genes. We conclude that ultrafine particles concentrate the proatherogenic effects of ambient PM and may constitute a significant cardiovascular risk factor.