Hyperlipidaemia may accelerate the development of atherosclerosis by enhancing the expression of chemokines by cells within the arterial wall. Chemokines of the CC subfamily are clearly implicated in atherogenesis; however, recent reports suggest that CXC chemokines may play a hitherto unrecognised role in monocyte recruitment into atheromatous lesions expressing these molecules. Here, we examine whether circulating levels of CXC chemokines may reflect the pathogenic changes occurring during early atherogenesis. ApoE*3 Leiden mice developed marked hypercholesterolaemia, and early Type I 'fatty streak' lesions, following consumption of an atherogenic diet high in saturated fat and cholesterol, and containing sodium cholate, for up to 4 weeks. By contrast, their non-transgenic littermates (C57BL/6J) exhibited a much less pronounced hypercholesterolaemia and did not develop fatty streak lesions, when fed the same diet. Under these conditions, serum concentrations of CXC chemokines, KC and Macrophage Inflammatory Protein-2 (MIP-2) were significantly (P<or=0.0005) elevated in apoE*3 Leiden mice consuming HFC/C diet, compared with apoE*3 Leiden mice consuming a chow diet. Further, serum concentrations of KC were significantly (P<0.02) higher at 4 weeks in apoE*3 Leiden mice fed HFC/C diet compared with their non-transgenic littermates consuming the same diet. Expression of KC mRNA was detected in both aortic and hepatic tissues of apoE*3 Leiden mice, and the non-transgenic controls. Thus, hypercholesterolaemia is associated with elevated serum concentrations of CXC chemokines, KC and MIP-2 that probably reflect chronic inflammation during atherogenesis.