Foam cell macrophage (FCM) formation is an early event in atherosclerosis that precedes both fibrous cap development and subsequent cap rupture; FCM have been implicated in both events. To understand this further we compared the transcriptomes of FCM and non-foamy macrophages (NFM) produced in subcutaneous sponges implanted into fat-fed ApoE null or C57Bl6 mice, respectively (n=4 each). RNA samples of high quality by A260/280>2 were compared on Illumina bead chips. Differential expression was classified as significant (p<0.05 after Bonferroni correction for multiple testing) or suggestive (p<0.001 unadjusted). 62 genes were significantly upregulated and 59 downregulated in FCM compared with NFM. A total of 370 and 381 genes were upregulated and downregulated using the more relaxed criterion. Fold changes confirmed by quantitative RT-PCR (n=5–7) included upregulation of cathepsin C (15×), cathepsin E (19×), matrix metalloproteinase (MMP)-2 (18×) and MMP-23 (22×) but also upregulation of tissue inhibitor of matrix metalloproteinase (TIMP)-2 (4×) and TIMP-3 (8×) and downregulation of MMP-13 (5×). Surprisingly, several matrix proteins were significantly upregulated, including collagen Iα1 (55×) and VIα1 (31×), osteonectin (72×) and biglycan (19×), although thrombospondin declined (2×). Hence our genomic analysis demonstrated changes that could lead to both matrix degradation and deposition. Ingenuity pathway analysis implicated activation of LXR/RXR in FCM, in agreement with other literature, and highlighted responses to platelet-derived growth factor and transforming growth factor β. The hypothesis that interaction of these pathways accounts for the ambiguous behaviour of FCM in matrix remodelling deserves further investigation.