Previous research on risk factors for obstructive heart defects (OHD) has focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interacting effects. Less is known about the role of paternal genetic variants or environmental exposures and the risk of OHD. We examined the effects of original parents in the transmission of alleles in genes of the folate, homocysteine ââpathway or transsulfurization on the occurrence of HDO in offspring. We used data from 569 families of live born infants with OHD born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-only case study. Maternal, paternal, and infant DNA were genotyped using a custom Illumina Golden Gate Single Nucleotide Polymorphism (SNP) panel. Relative risk (RR), 95% confidence interval (CI) and likelihood ratio tests from log-linear models were used to estimate the original parent effect of 877 SNPs in 60 candidate genes in folate, homocysteine ââand transsulfurization pathways on OHD risk. Bonferroni’s correction was applied for multiple tests. We identified 3 SNPs in the transsulfurization pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternal copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, the RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16 x 10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80 x 10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28 x 10-5), and 0.34 (95% CI: 0.20 , 0.58, P = 3.77×10-5), respectively, compared to infants who inherited mother-derived copies of the same alleles. We observed a statistically significant decrease in the risk of OHD in infants who inherited paternal genetic variants involved in the folic acid and transsulfurization pathways.