Prenatal folate and vitamin B₁₂ status have been linked to child neuropsychological development, but less is known about maternal genetic influences on this association. We conducted an exploratory longitudinal study of 181 mother–child pairs to assess whether maternal MTHFR 677C>T genotype modifies the association between maternal plasma folate and vitamin B₁₂ in the first trimester of pregnancy and child neuropsychological development. Maternal plasma folate and vitamin B₁₂ were determined by radioimmunoassay, and MTHFR 677C>T genotypes by PCR. We evaluated child neuropsychological development at 1, 3, 6, 12, 18, 24, and 30 month old using the Bayley Scales of Infant Development II. We analyzed the data using mixed-effects multivariate linear regression. The MTHFR 677C>T genotype distribution among the mothers was 18.2% CC, 49.8% CT, and 32.0% TT. The Mental Development Index (MDI) was inversely associated with maternal plasma folate among offspring of MTHFR 677CC mothers (β = -2.18 per twofold increase, 95% CI -4.07; -0.30, corrected P value = 0.02); no significant associations were observed among children born to women of other genotypes. The Motor Development Index (PDI) was not significantly associated with maternal plasma folate in any maternal MTHFR 677C>T genotype group, nor were MDI or PDI significantly associated with maternal plasma vitamin B₁₂ in any maternal MTHFR 677C>T genotype group. This study suggests that maternal MTHFR 677CC genotype interacts with first-trimester plasma folate to influence offspring mental development.