Long-term exercise is associated with reduced atherosclerotic burden, inflammation, and enhanced endothelial progenitor cell (EPC) levels in mice. Infusion of progenitor cells in mice decreases atherosclerosis and suppresses inflammation. The aim of this study was to determine whether exercise-induced enhancement of EPCs is associated with reduced atherosclerosis and inflammation. To study this, 20-week old ApoE(-/-) mice with advanced atherosclerotic lesions (n = 12/group) were randomized to voluntary running or no running for 8 weeks. Exercise led to a potent suppression of elevated circulating proinflammatory cytokines without significant reduction of atherosclerotic lesions. When repeated in ApoE(-/-) mice with early atherosclerotic disease, exercise led to a 62% (p = 0.017) reduction in lesion thickness (intima-to-media ratio) at the aortic root. Interestingly, BM-EPC levels were significantly elevated under proinflammatory conditions seen in ApoE(-/-) mice and decreased in response to exercise, independent of the degree of atherosclerosis. Under early atherosclerotic conditions, long-term exercise reduces atherosclerotic plaque burden and is associated with reduced systemic inflammation. Elevated BM-EPCs seen in atherosclerotic conditions may be a marker of generalized vascular inflammation or injury, and decrease in response to exercise, along with other markers of inflammation.