Oxidation and other modifications of serum low-density lipoprotein (LDL) are associated with the development of atherosclerosis, and a scavenger receptor and CD40 signalling are also known to play important roles in the process. We previously showed that the Src family protein-tyrosine kinase Lyn is physically and/or functionally associated with macrophage type-I and type-II class-A scavenger receptors (MSR-A) and CD40. In this study, we addressed whether Lyn is involved in the build-up of serum lipid levels and in atherosclerotic changes. When fed a normal diet, lyn-deficient mice had serum lipid levels that were no different from those of wild-type mice. By contrast, lyn-deficient mice fed a high-fat diet showed serum lipid levels that were much higher than those seen in wild-type mice. Curiously, however, the lyn-deficient mice fed either diet showed no increase in incidence of atherosclerotic lesions compared with wild-type mice. This may be partly explained by our data showing suppression of proliferation of peritoneal macrophages in response to oxidized LDL in the absence of Lyn, and failure of stimulation of the CD40 pathway in lyn-deficient macrophages to induce expression of monocytic chemoattractant protein-1 (MCP-1), which is related to atherosclerosis. These results suggest that Lyn plays an important role in the metabolism of serum lipids and in the development of atherosclerotic lesions on high-fat diets.