Exposure to arsenic results in a wide variety of adverse effects. It has been postulated that one mechanism of arsenic toxicity is disruption of cellular methyl biochemistry. Because dietary folate is required to generate the methyl donor S-adenosyl methionine, we hypothesized that loss of folate binding protein 2 (Folbp2) results in increased susceptibility to arsenic-induced cytotoxicity. Using Folbp2 +/+ and -/- fibroblasts, we determined that Folbp2 null cells display increased sensitivity to arsenic exposure. Folic acid supplementation partially rescues wild type cells from arsenic toxicity, but Folbp2 null cells are not protected. Arsenic inhibits folic acid uptake in Folbp2 null fibroblasts, but not wild type cells; baseline uptake is similar in both cell types. These results support the possibility that arsenic toxicity occurs, in part, by perturbing cellular methyl biochemistry. Furthermore, identification of Folbp2 as a protective protein presents an opportunity to identify populations at increased risk for serious effects of arsenic exposure.