Objective— Our laboratory has previously created 2 strains of rabbits with genetically determined high-atherosclerotic response (HAR) and low-atherosclerotic response (LAR). The aim of the present study was to identify new genes of atherosclerosis susceptibility in macrophages from the 2 strains. Methods and Results— Suppression subtractive hybridization was used to screen for genes with higher expression in macrophages from LAR rabbits. We identified a cDNA fragment with high homology to human arginase I (AI; 91%) and subsequently cloned the full-length cDNA of the rabbit homologue. Quantitative RT-PCR revealed a significantly higher macrophage AI mRNA expression in LAR rabbits than in HAR rabbits (77428±10941 versus 34344±4538; P =0.002; copies/10 ⁶ copies β-actin), which also correlated with a significantly higher arginase enzyme activity. Northern blot analysis led to the identification of a size polymorphism of AI mRNA. This was because of a 413 bp C-repeat insertion in the 3′ untranslated region. The shorter transcript variant was predominantly expressed in LAR rabbits and associated with significantly higher AI mRNA expression levels. Transfection experiments indicated decreased mRNA stability of the long AI variant. Conclusions— High expression of arginase I in macrophages may contribute to atherosclerosis resistance of LAR rabbits, possibly by conferring antiinflammatory effects in the vessel wall.