In non-clinical low-risk populations 15% of infants show disorganized attachment behavior(1,2) with their caregivers in the Strange Situation,(3) a mildly stressful laboratory procedure testing infants' ability to cope with separation anxiety. Disorganization of early attachment has been primarily ascribed to inadequate parenting,(2,4,5) and has been associated with childhood behavior problems(6,7)and adolescent psychopathological tendencies.(5) We have recently reported an association between the DRD4 exon III 48 basepair repeat polymorphism and disorganization of infants' attachment behavior towards their mother in a low-social-risk group of 1-year-old infants:(8) the risk for disorganized attachment among infants carrying the 7-repeat allele was fourfold. Here we report further evidence for the involvement of the dopamine D4 receptor gene in attachment disorganization. The same group of infants was genotyped for the functional -521 C/T single nucleotide polymorphism (SNP) in the upstream regulatory region of the DRD4 gene(9) in order to test the association with attachment disorganization both alone and in interaction with the DRD4 exon III 7-repeat allele. While the -521 C/T genotype itself had no effect on attachment status (chi(2) = 0.41, df = 2, P = 0.82), there was an interaction between the structural 48-bp repeat polymorphism and the -521 C/T promoter polymorphism: the association between disorganized attachment and the 7-repeat allele was enhanced in the presence of the -521 T allele (chi(2) = 6.61 and 6.67, df = 1, P < 0.025 for CT and TT genotypes, respectively). In the presence of both risk alleles the odds ratio for disorganized attachment increased tenfold. This result supports our previous postulation that the DRD4 gene plays a role in the development of attachment behavior in low-risk, non-clinical populations.