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This study investigated the impact of high folate intake, alone or with methylenetetrahydrofolate reductase (MTHFR) deficiency, on embryonic and placental development in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p><jats:italic>Mthfr<\/jats:italic> +\/+ or +\/\u2212 pregnant mice on a control diet (CD; recommended intake of folic acid for rodents) or folic acid\u2010supplemented diet (FASD; 20\u2010fold higher than the recommended intake) were examined for embryonic loss, delay, and defects at 10.5 and 14.5 days post coitum (dpc); 10.5\u2010dpc placenta, and 14.5\u2010dpc embryo hearts were studied histologically.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Total plasma folate was 10\u2010fold higher in FASD compared to CD mice; plasma homocysteine levels were not affected by diet. At 10.5 dpc, the FASD was associated with embryonic delay and growth retardation, and may confer susceptibility to embryonic defects. The FASD did not adversely affect 10.5\u2010dpc placental development. At 14.5 dpc, embryos from the FASD <jats:italic>Mthfr<\/jats:italic> +\/+ group were delayed and the FASD was associated with thinner ventricular walls in embryonic hearts. There was a significant interaction between maternal MTHFR deficiency and a high folate diet for several developmental outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Our study suggests that high folate intake may have adverse effects on fetal mouse development and that maternal MTHFR deficiency may improve or rescue some of the adverse outcomes. These findings underscore the need for additional studies on the potential negative impact of high folate intake during pregnancy. 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