Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both have been implicated in atherosclerosis, the pathological role of signalling cascades downstream of IL-6 is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 signalling cascade, here we evaluate whether gp130-dependent STAT3 activation modulates atherosclerosis. High-fat diet-induced atherosclerosis was established in ApoE −/− mice crossed with gp 130 F / F knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp 130 F / F :Stat3 −/+ :ApoE −/− mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE −/− and gp 130 F / F :ApoE −/− mice. At 10 weeks post high-fat diet, aortic atherosclerotic lesions, including the presence of CD68 + macrophages, and plasma lipid and SAA profiles, were assessed. Aortic plaque development and plasma triglyceride levels in gp 130 F / F :ApoE −/− mice were significantly reduced (3-fold, P < 0.001) compared to ApoE −/− littermates. By contrast, in gp 130 F / F :ApoE −/− mice, atherosclerotic plaques contained augmented CD68 + macrophage infiltrates, and plasma SAA levels were elevated, compared to ApoE −/− mice. Atherosclerotic lesion development and plasma triglyceride levels in gp 130 F / F :ApoE −/− and gp 130 F / F :Stat3 −/+ :ApoE −/− mice were comparable, despite a significant ( P < 0.05) reduction in macrophage numbers in lesions, and also plasma SAA levels, in gp 130 F / F :Stat3 −/+ :ApoE −/− mice. Finally, aortic plaque development and plasma triglyceride levels were comparable in ApoE −/− mice reconstituted with gp 130 F / F :ApoE −/− (ApoE F / F :ApoE) or ApoE −/− (ApoEApoE) bone-marrow cells. Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques.