The internal mammary arteries (IMA) are resistant to the development of atherosclerosis. By contrast, the coronary arteries (Cor) are athero-prone. The IMA is “the gold standard” for bypass grafting because of its lack of disease and long term patency. The purpose of our research is to examine the genetic profile of the IMA in an effort to explain its resistance to disease. We have gone from basic science expression profiling to direct clinical observations in human subjects (n=10). Microarray analysis showed 95 genes differentially expressed in the ECs of IMA vs Cor. The most statistically significant different gene was the adenosine A2B receptor, expressed in endothelial cells (EC). The transcription and translation of Western blot analysis showed higher A2B expression in the IMA than in coronary arteries which became down-regulated with progressive atherosclerosis. In vitro, the overexpression of A2Bin ECs rescued the cells from disease: it blunted monocyte adhesion, cell adhesion molecule expression, EC migration, and the trans-endothelial migration of monocytes-- processes directly associated with the development of atherosclerosis. Knockdown of A2B expression by siRNA promoted these processes. Conclusions—ECs derived from the IMA and Cor are distinctly different in gene expression, which may be responsible for their differential sensitivities for atherosclerosis. This study defined how the A2B receptor may act as an atherosclerotic-resistance gene in the IMA, which blunted monocyte adhesion and cell adhesion molecule expression, EC migration and retarded the transendothelial migration of monocytes.