We used the ADVIA 2120 Hematology System (Bayer HealthCare, Diagnostics Division, Tarrytown, NY) to study the effects of vigorous exercise on CBC count, WBC differential, RBC fragmentation, and platelet activation parameters in 32 healthy participants in a 26.2-mile (42.2-km) marathon. The runners demonstrated increases in hematocrit and platelet count consistent with dehydration and leukocytosis indicative of demargination of neutrophils or inflammation secondary to tissue destruction (eg, rhabdomyolysis). The number of RBC fragments was increased after the race (P = .008), consistent with exercise-induced hemolysis. The mean platelet component, a measure of platelet granularity, was decreased (P < .0001), and the number of platelet clumps was increased (P = .0026), providing evidence for in vivo platelet activation during the marathon. By using direct measurement of platelet granularity, our study confirms the in vivo activation of platelets by vigorous exercise and establishes the usefulness of automated cell counters for the assessment of platelet activation and of RBC fragmentation in this setting.