AbstractAttention‐deficit/hyperactivity disorder, ADHD [MIM 126452], is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness, and/or inattentiveness. As part of an ongoing study of ADHD, we carried out a family‐based discordant sib‐pair analysis to detect possible associations between dopamine receptor D4 (DRD4) and dopamine transporter 1 (DAT1) polymorphisms and ADHD in Chilean families. Both loci individually classified as homozygotes or heterozygotes for the DRD4 7‐repeat and DAT1 10‐repeat alleles, did not exhibit genotype frequency differences between affected children and their healthy siblings (Fisher's exact test P > 0.25 in both cases). However, the simultaneous presence of both DRD4 7‐repeat heterozygosity and DAT1 10 allele homozygosity were significantly higher (34.6%) in cases (26), compared with their unaffected siblings (25) (4%; Fisher's exact test P = 0.0096; odds‐ratio, OR = 12.71). Increased density of dopamine transporter in ADHD brains, along with abundance of 7‐repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene–gene interaction worthy of further incisive studies. © 2005 Wiley‐Liss, Inc.