The association between sickle cell trait (SCT) and adverse effects of exercise has been controversial. While individuals with SCT are at higher risk of sudden death, the mechanism for this outcome remains to be elucidated. In order to shed light on this controversy, we have monitored venous blood count and blood gas parameter values in normal and SCT subjects during treadmill exercise. White and red blood cell counts and hemoglobin changed significantly over time in both the SCT and normal groups, with peak exercise values different from pre-exercise or post-exercise values. Red blood cell counts showed significant group-time interaction; increase in count during exercise was accentuated in SCT subjects. All blood gas parameters showed significant changes over time in both groups. O2 content was significantly higher in SCT than AA at all time intervals. O2 saturation, pO2 and CO binding to hemoglobin showed significant group-time interaction. Furthermore, O2 saturation for the combined groups was significantly greater at peak exercise and at rest than before exercise. It is possible that treadmill exercise causes microvascular shunting in SCT subjects, leading to a decrease in the peripheral utilization of oxygen.