Autism spectrum disorder (ASD) may be associated with abnormalities in folate metabolism, which is a process that affects genetic expression by facilitating the formation of methyl donors for DNA methylation. Limited data show that some children with ASD show behavioral improvements with folic acid (FA) therapy, while others show a worsening effect. If behavioral worsening is linked with abnormalities in folate metabolism, then nutritional modifications could normalize these processes and result in clinical improvements. To address this premise, a randomized, placebo-controlled crossover pilot study with two phases is proposed. The first phase will focus on the behavioral and biochemical responses of children with ASD to high-dose folic acid supplementation. Because FA is an inactive folate that requires biochemical conversion to become active, and select genotypes impede this conversion, the hypothesis is that FA will yield behavioral improvements in some children but exacerbate problem behaviors in others. During the second phase, children who had a worsened behavioral response to FA during phase 1 will participate in an open-label trial of high-dose Metafolin (an active folate metabolite) supplementation. Results from this project may provide support for continued study of the potential relationship between folate metabolism and problem behaviors among children with ASD, potentially justifying the need to examine effects of folate supplementation among a larger sample of affected children.