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Intravenous and/or intrathecal administration of the anti-folate drug methotrexate is a common chemotherapeutic procedure in childhood leukemia. Therapeutic and prophylactic efficacy of these procedures notwithstanding, the occurrence of late adverse effects remains a cause of clinical concern in leukemia survivors. We propose an experimental mouse model to mimic the impact of methotrexate exposure on brain biochemistry and cell proliferation, as well as behavioral and neurocognitive functioning at adult age. Female C57Bl6/J mouse pups received saline or methotrexate injection (20 mg/kg, i.p.). CSF and serum concentrations of folate metabolites and toxicity makers were analyzed at 4 h, 24 h, and 1 week following injection. Behavioral test battery performance was assessed at adult age (3-4 months). We found acute changes in serum and CSF levels of folate in exposed pups that coincided with increases in CSF Tau, whereas homocysteine in serum and CSF, and CSF levels of pTau were unchanged or remained below detection. In addition, methotrexate injection coincided with diminished hippocampal cell proliferation 1 week after methotrexate injection. At adult age, exposed mice displayed hippocampus-dependent deficits in the Morris water maze, whereas exploration and anxiety-related behaviors were largely unaffected. Particularly during the reference memory (probe) trial after reversal learning, methotrexate-exposed animals were less precise than controls. These findings demonstrate adult neurocognitive sequelae in a mouse model that can be attributed to the biochemical and cellular impact of early-life methotrexate exposure., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)