To test the possibility that variations in macrophage lipoprotein lipase (LPL) secretion may constitute one of the hereditary components of atherosclerosis, we evaluated LPL gene expression and secretion in macrophages harvested from inbred mouse strains differing in their susceptibility to the diet-induced development of atherosclerosis. Inflammatory peritoneal macrophages harvested from atherosclerosissusceptible C57BL/6J mice showed twofold to threefold higher basal LPL mass, activity, and mRNA levels than those isolated from atherosclerosis-resistant C3H/HeN mice. We determined LPL secretion and gene expression in the susceptible C57BL/6J (B), resistant A/J (A), and AxB/BxA recombinant inbred strains of mice typed as atherosclerosis resistant (A-like) or atherosclerosis susceptible (B-like). Macrophage LPL secretion and mRNA expression were twofold higher in the susceptible C57BL/6J (B) mice than in the resistant A/J (A) mice. Significantly higher LPL secretion, activity, and gene expression were found in recombinant inbred mouse strains that typed B-like than in those typed A-like. These results indicate that susceptibility to atherosclerosis is associated in inbred mouse strains with high LPL secretion and mRNA levels, whereas lower LPL secretion and mRNA expression are observed in atherosclerosis-resistant mice. These observations suggest a contributive role for LPL in the development of atherosclerosis.