Atherosclerotic lesions are characterized by prominent macrophage and T-cell infiltration and atherosclerosis is widely recognized as an inflammatory disease. The cytokine interleukin-15 (IL-15) has T-cell chemotactic and pro-inflammatory properties and promotes the recruitment of T cells to sites of inflammation. We have therefore examined IL-15 expression in the atherosclerotic ApoE-deficient mouse model as well as in human atherosclerotic lesions. In gene expression arrays, a transcript corresponding to IL-15 mRNA was elevated in atherosclerotic aortas of ApoE-deficient mice fed a Western diet for 10 and 20 weeks, corresponding to lesions of the fatty streak and fibrofatty plaque stage, respectively. Immunostaining for IL-15 localized to aortic smooth muscle cells in nonatherosclerotic C57BL/6 mice, whereas both macrophages and smooth muscle cells stained positive for IL-15 in atherosclerotic lesions of ApoE-deficient mice. Finally, advanced atherosclerotic lesions of human carotid arteries were immunostained to determine whether IL-15 is involved in human disease. IL-15 protein was present also in the human lesions with a distribution primarily overlapping that of macrophages. In conclusion, IL-15 is up-regulated in both human and animal atherosclerotic lesions and may contribute to the recruitment of T cells and their activation during atherogenesis.