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Introduction Inorganic arsenic (iAs) is the chemical form of As commonly found in drinking water (ATSDR 2007) and in some foods (Cubadda et al. 2017). Chronic exposure to iAs has [...], Background: Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risks of iAs-induced diseases. Mechanisms underlying these diseases have been extensively studied using animal models. However, substantive differences between humans and laboratory animals in efficiency of iAs methylation have hindered the translational potential of the laboratory studies. Objectives: The goal of this study was to determine whether humanization of the As3mt gene confers a human-like pattern of iAs metabolism in mice. Methods: We generated a mouse strain in which the As3mt gene along with the adjacent Borcs7 gene was humanized by syntenic replacement. We compared expression of the mouse As3mt and the human AS3MT and the rate and pattern of iAs metabolism in the wild-type and humanized mice. Results: AS3MT expression in mouse tissues closely modeled that of human and differed substantially from expression of AS3MT. Detoxification of iAs was much less efficient in the humanized mice than in wild-type mice. Profiles for iAs and its methylated metabolites in tissues and excreta of the humanized mice were consistent with those reported in humans. Notably, the humanized mice expressed both the full-length AS3MT that catalyzes iAs methylation and the human-specific [AS3MT.sup.d2d3] splicing variant that has been linked to schizophrenia. Conclusions: These results suggest that AS3MT is the primary genetic locus responsible for the unique pattern of iAs metabolism in humans. Thus, the humanized mouse strain can be used to study the role of iAs methylation in the pathogenesis of iAs-induced diseases, as well as to evaluate the role of [AS3MT.sup.d2d3] in schizophrenia. https://doi.org/10.1289/EHP6943