Atherosclerosis is a disease of both lipids and inflammatory immune cells. More specifically, elevated plasma levels of low-density lipoproteins (LDL) ultimately lead to migration of circulating monocytes into the artery wall. Lipid-loaded monocytes proliferate and become macrophage foam cells, the hallmark of atherosclerotic lesions. A proposed mechanism for the protective effects of high-density lipoprotein (HDL) is apolipoprotein A-I (apoA-I) acting as a mediator of cholesterol efflux from cells and subsequent foam cell regression. To better understand the biological changes stimulated by apoA-I treatment, differential gene expression analysis of microarray data was performed on spleen cells from mice treated with recombinant HDL (rHDL). LDL receptor null (LDLr-/-) and LDL receptor and apoA-I null (LDLr-/-, apoA-I-/-) mice were fed a Western diet consisting of 0.2% cholesterol and 42% calories as fat (HF) for a total of 12 weeks. After six weeks of diet, a subset of mice for each genotype was subcutaneously injected with 200 micrograms of rHDL (protein weight) three times a week for the remaining six weeks. The control group of mice was subcutaneously injected with 200 micrograms of bovine serum albumin (BSA). Spleen cell RNA was isolated, purified, and analyzed via Illumina BeadArray Microarray Technology. Individual differential gene expression analysis that contrasted treated to non-treated groups for each genotype was performed. LDLr-/-, apoA-I-/- rHDL treated mice showed 281 significantly differentially expressed genes compared to non-treated mice while LDLr-/- mice had 1502 such genes. Of the significant genes, 189 intersected across both genotypes. In LDLr-/-, apoA-I-/-, 73 of these were up-regulated and 116 were down-regulated. LDLr-/- similarly showed 71 of the intersected genes to be up-regulated and 118 to be down-regulated. One-directional gene set pathway analysis was also performed. LDLr-/-, apoA-I-/- treated mice revealed 49 significant pathways while LDLr-/- showed a total of 63. Of these, 21 were up-regulated and 14 were down-regulated in both genotypes. Of the overrepresented, up-regulated pathways, eight of the top ten most significant ones were related to immune cells. Major functions involved receptor, adhesion, and chemokine signaling. Overall, preliminary analysis suggests apoA-I treatment induces similar gene expression changes across different genotypes in mouse spleen cells.