The complement anaphylatoxin C5a functions through its two receptors, C5aR (CD88) and C5a receptor-like 2 (C5L2). Their role in atherosclerosis is incompletely understood. We, therefore, analyzed C5aR and probed the yet unknown expression and function of C5L2 in human atherogenesis. Human atherosclerotic plaques obtained by endarterectomy were staged and analyzed for C5L2 and C5aR by IHC and quantitative real-time PCR. C5L2-expressing cells in plaques were mostly macrophages, less neutrophils and endothelial cells, as determined by double immunostaining. Although early influx of C5aR(+) cells was detected, C5L2 levels increased with lesion complexity and colocalized with C5aR and oxidized low-density lipoprotein. Gene expression of C5L2 and C5aR showed similar trends, such as the receptor-expressing cells. The expression of C5L2 in advanced lesions correlated with increased levels of IL-1β and tumor necrosis factor-α in plaques. Furthermore, in vitro experiments in macrophages from wild-type and C5l2- and C5ar-deficient mice corroborated the contributing role of C5l2 in oxidized low-density lipoprotein-pretreated C5a-induced cytokine expression, as measured by enzyme-linked immunosorbent assay. Finally, C5l2- and C5ar-deficient peripheral blood mononuclear cells showed less arrest on tumor necrosis factor-α-stimulated mouse endothelial cells in vitro when compared with wild-type controls. Taken together, prominent C5L2 expression in advanced atherosclerotic stages directly correlates with high levels of proinflammatory cytokines. This might indicate a proinflammatory role of C5L2 in atherosclerosis that needs to be pursued in the future by applying in vivo mouse models.