Numerous studies have implicated C-reactive protein (CRP) and the acute phase response (APR) in the development of atherosclerotic heart disease. Interleukin (IL)-6, which regulates both CRP expression and the APR, has also been identified as a risk factor for heart disease. To more directly evaluate the role of IL-6 in the development of atherosclerosis, IL-6 knockout mice were crossed with atherosclerosis prone LDL receptor (LDL-R) knockout mice. Lesion development was evaluated on Chow, Western type and Paigen diets. As anticipated, the Paigen diet stimulated the expression of APR genes in LDL-R[-/-] mice, but not IL-6[-/-]/LDL-R[-/-] mice. Despite this difference in acute phase response, only modest and statistically not significant differences were noted in the development of atherosclerotic lesions in LDL-R[-/-] and IL-6[-/-]/LDL-R[-/-] mice. These observations suggest that IL-6 and the acute phase response may not play as significant role in atherogenesis as other studies have indicated.