Examining the joint effect of two functional variants in two dopamine-related genes (DRD3 and COMT) on ADHD-relevant behaviors under three experimental conditions (EC). 362 children with ADHD were assessed by parents and teachers during a week of baseline evaluation, followed by 1 week of MPH and placebo, administered in a double-blind crossover design. Statistically significant 3-way (DRD3-by-COMT-by-EC; p = .004) and 2-way interactions (COMT by EC; p = .002) were observed on Conners'-Teachers scores. Children with the COMT Met/Met genotype had lower scores at baseline and on placebo compared to the other genotype groups. Furthermore, stratifying the children according to their COMT genotypes helped to detect statistically significant and biologically meaningful effects of DRD3 genotype. These findings suggest that COMT and DRD3 genetic variants may together play a role in ADHD symptomatology and response to treatment through gene-gene interaction.