Microdeletion 22q11 syndrome (del22q11)has an estimated incidence of 1/4000 and is a common known cause of congenital heart disease (CHD). Approximately 50-70% of patients have CHD. Most patients have a deletion of similar size and location; the reason for the incomplete penetrance of the cardiovascular anomalies is unknown. Low maternal folate levels and variants in folate metabolism genes have been associated with increased risk of non-syndromic CHD. We evaluated the association of 7 variants in 6 folate metabolism genes in 112 Chilean patients with del22q11. The patients, 50% of them with CHD, and their parents, were genotyped for variants C677T and A1298C in the MTHFR gene, A80G in SLC19A1, G1958A in MTHFD1, G742A in BHMT, A2756G in MTR and A66G in MTRR. We found marginal evidence of association of CHD with maternal allele 80G in the SLC19A1 gene: its allelic frequency was 0.72 in mothers of children with CHD and 0.44 in mothers of children without CHD (uncorrected p value 0.03; RR 1.35 (95% CI 0.997-1.855). There were no statistically significant differences in allelic or genotypic frequencies for any of the other variants. SLC19A1 is involved in intestinal folate transport, the 80G allele decreases its efficiency and this may affect maternal folate absorption. The association found in this study suggests that maternal abnormalities in folate metabolism could modify the risk of cardiovascular abnormalities in patients del22q11.