Exposure to fine airborne particulate matter (PM_2.5) is associated with cardiovascular events and mortality in older and cardiac patients. Potential physiologic effects of in-vehicle, roadside, and ambient PM_2.5 were investigated in young, healthy, nonsmoking, male North Carolina Highway Patrol troopers. Nine troopers (age 23 to 30) were monitored on 4 successive days while working a 3 P.M. to midnight shift. Each patrol car was equipped with air-quality monitors. Blood was drawn 14 hours after each shift, and ambulatory monitors recorded the electrocardiogram throughout the shift and until the next morning. Data were analyzed using mixed models. In-vehicle PM_2.5 (average of 24 μg/m³) was associated with decreased lymphocytes (−11% per 10 μg/m³) and increased red blood cell indices (1% mean corpuscular volume), neutrophils (6%), C-reactive protein (32%), von Willebrand factor (12%), next-morning heart beat cycle length (6%), next-morning heart rate variability parameters, and ectopic beats throughout the recording (20%). Controlling for potential confounders had little impact on the effect estimates. The associations of these health endpoints with ambient and roadside PM_2.5 were smaller and less significant. The observations in these healthy young men suggest that in-vehicle exposure to PM_2.5 may cause pathophysiologic changes that involve inflammation, coagulation, and cardiac rhythm.