Many studies have reported associations between air pollution particles with an aerodynamic diameter <2.5 μm (fine particulate matter (PM)) and adverse cardiovascular effects. However, there is an increased concern that so-called ultrafine PM which comprises the smallest fraction of fine PM (aerodynamic diameter <0.1 μm) may be disproportionately toxic relative to the 0.1–2.5 μm fraction. Ultrafine PM is not routinely measured in state monitoring networks and is not homogenously dispersed throughout an airshed but rather located in hot spots such as near combustion sources (e.g., roads), making it difficult for epidemiology studies to associate exposure to ultrafine PM with adverse health effects. Thirty four middle-aged individuals with metabolic syndrome were exposed for 2 h while at rest in a randomized crossover design to clean air and concentrated ambient ultrafine particles (UCAPS) for 2 h. To further define potential risk, study individuals carrying the null allele for GSTM1 (a prominent antioxidant gene) were identified by genotyping. Blood was obtained immediately prior to exposure, and at 1 and 20 h afterward. Continuous Holter monitoring began immediately prior to exposure and continued for 24 h. Based on changes we observed in previous CAPS studies, we hypothesized that ultrafine CAPS would cause changes in markers of blood inflammation and fibrinolysis as well as changes in heart rate variability and cardiac repolarization. GSTM1 null individuals had altered cardiac repolarization as seen by a change in QRS complexity following exposure to UCAPS and both the entire study population as well as GSTM1 null individuals had increased QT duration. Blood plasminogen and thrombomodulin were decreased in the whole population following UCAPS exposure, whereas C-reactive protein (CRP) and SAA were increased. This controlled human exposure study is the first to show that ambient ultrafine particles can cause cardiovascular changes in people with metabolic syndrome, which affects nearly a quarter of the U.S. adult population.