Small size at birth continues to be a problem worldwide and many factors, including reduced folate intake and Pb exposure, are associated with it. However, single factors rarely explain the variability in birth weight, suggesting a need for more complex explanatory models. We investigated environment–gene interactions to understand whether folate intake and maternal Pb exposure were associated with smaller newborn size in 474 women with uncomplicated pregnancies delivering term infants in Mexico City. We examined if folate intake modified the negative effects of maternal Pb burden on birth size. We also asked if maternal and infant methylenetetrahydrofolate reductase (MTHFR) genotypes (C677T, A1298C and G1793A) modified the effects of folate intake or Pb exposure on birth size. Women were aged 24·6 (sd 5·1) years; 43·5 % were primiparous. Maternal blood Pb at delivery was 86 (sd 42) μg/l, with 26·7 % having levels ≥ 100 μg/l. Tibia Pb level was 9·9 (sd 9·8) μg/g. Of the women, 35·3 % had folate intakes < 400 μg/d. Birth weight was 3170 (sd 422) g. In covariate-adjusted regressions, higher folate intake was associated with higher birth weight (β 0·04; P < 0·05). Higher bone Pb was associated with lower birth weight (β − 4·9; P < 0·05). Folate intake did not modify the effects of Pb on birth size, nor did MTHFR modify the association between Pb or folate intake on birth size. Although modest, the relationship between maternal nutrition, Pb burden and birth size does underscore the importance of environmental exposures to child health because patterns of fetal growth may affect health outcomes well into adulthood.