Abstract Hepatic macrophages play an essential role in the granulomatous response to infection with the parasitic helminth Schistosoma Mansoni, but the transcriptional changes that underlie this participation are poorly understood. To explore this, we sorted the two previously recognized hepatic macrophage populations (perivascular and Kupffer) from naïve and S. mansoni infected mice and performed microarray analysis as part of the Immunological Genome Project. Consistent with the pattern of great diversity identified in other organ macrophages, the two hepatic macrophage populations displayed signatures distinct from all other macrophages, with the two populations exhibiting remarkable differences between them. However, this diversity was greatly reduced following infection with S. mansoni, and in fact, many of the transcripts identified as uniquely perivascular or Kupffer cell specific were lost following infection, raising the possibility that both populations may be replenished by monocytes following infection. Our analysis showed a profound alteration in phospholipid and cholesterol metabolic pathways, including prostaglandin signaling, in addition to the expected M2 markers. These changes suggested a possible mechanism for the previously reported atheroprotective effects of S. mansoni infection. Indeed we find that ApoE null mice fed a high fat diet in combination with S. mansoni infection have reduced body mass in addition to reduced plaque area as compared to control mice.