Inorganic arsenic (iAs) is a common drinking water contaminant and transplacental carcinogen in mice, and possibly in humans. Recent animal studies suggest the mechanism of iAs carcinogenesis may include competition for S-adenosylmethionine required for both iAs and fetal DNA methylation, causing aberrant gene expression and cancer in adulthood. We exposed mouse dams to 0 or 85ppm iAs in drinking-water while feeding them a diet containing either 2.2 or 11mg/kg of folate. At gestational day (GD) 18, we examined DNA methylation patterns in fetal livers using CpG-island microarrays. Our results show that compared to folate supplementation alone, combined exposure to iAs and folate dramatically increased the number of CpG islands with altered methylation patterns. The most affected genes were associated with the cancer, neurological development, and cell signaling networks. This data raises concern about the efficiency and potential risks associated with folate supplementation in human populations chronically exposed to iAs.