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There is no FDA approved treatment that addresses underlying ASD pathophysiology and/or core deficits. However, emerging evidence indicates that leucovorin, a form of folate that bypasses physiological blocks found in ASD, can significantly improve verbal communication as well as associated symptoms. Our double blind placebo controlled (DBPC) trial published in Molecular Psychiatry, found that leucovorin significantly improved verbal communication in children with ASD with a medium-to-large effect size especially in the subset positive for the folate receptor autoantibody (FRAA+). Positive effects were also seen on the secondary outcome measure of social withdrawal. We hypothesize that leucovorin could impact social communication if treatment is initiated early, when neuroplasticity is greater and social communication is being established. We propose a multisite DBPC trial with open-label extension of leucovorin in 2½-5 year old FRAA+ children with ASD. Our primary outcome will be the Brief Observation of Social Communication Change, a sensitive, validated, direct assessment of change in social communication developed by C. Lord at the Center for Autism and the Developing Brain. We will also measure neuronal activation and connectivity using non-invasive neuroimaging. If leucovorin can be shown to improve the core deficit of social communication in ASD, the potential positive impact will be significant, laying the groundwork for a precision medicine approach to ASD treatment.