The concentration of particles in the ambient air is associated with deaths from cardiovascular disease, and determining the biologic mechanisms involved has been identified as a high-priority research need. Hypotheses have focused on the possibility of direct cardiac effects, or indirect effects related to inflammatory responses, including increased blood viscosity or increased blood coagulability. Ultrafine particles (UFPs; those smaller than 100 nm) may be important in cardiovascular effects because of their very high deposition efficiency in the pulmonary region, and their high propensity to penetrate the epithelium and reach interstitial sites. We have initiated human clinical studies of the health effects of UFPs using a mouthpiece exposure system. Healthy, nonsmoking subjects 18-55 years of age are exposed at rest for 2 hr to 10 microg/m3 carbon UFPs and to filtered air as a control. Preliminary findings indicate a relatively high overall deposition fraction (0.66 +/- 0.12 by particle number) consistent with model predictions and an absence of particle-associated symptoms or changes in lung function. Planned studies examine responses in susceptible subject groups, and the effects of particles of varying composition. Human clinical studies using model particles will complement other approaches such as epidemiologic, animal exposure, and in vitro studies in determining the mechanisms for heath effects related to ambient particle exposure.