BACKGROUND: Methylphenidate (MPH) blocks the norepinephrine transporter as well as the dopamine transporter. The alpha-2a-adrenergic receptor is a key component of the noradrenergic system. The aim of this study was to evaluate the association between the ADRA2A -1291 C>G polymorphism and the response to MPH treatment in Korean subjects with attention-deficit/hyperactivity disorder (ADHD). METHODS: This study enrolled 114 ADHD children (mean age = 9.08 +/- 1.94 years) from a child psychiatric clinic in South Korea. Subjects who had an improvement of >/= 50% compared with the baseline ADHD rating scale (ARS) score or who had a Clinical Global Impression-improvement score of 1 or 2 points after treatment were defined as the "good response". We examined the relationship of the ADRA2A to MPH response. RESULTS: We found that a good response to MPH treatment, measured by the ARS as assessed by the parents, was observed for 76.9% of the subjects carrying the G/G genotype but for only 46.0% and 41.7% of those with the C/G and C/C genotypes, respectively [chi(2)(2) = 11.929, p = .003]. We also found a significant difference in the change in total ARS scores between subjects with and without the G/G genotype [t(1) = 2.21, p = .029]. CONCLUSIONS: Our findings provide evidence of an association between the ADRA2A -1291 C>G genotype and response to MPH treatment in Korean subjects with ADHD. Nonetheless, the methodological limitation of not being a randomized placebo-controlled trial and primarily basing results on parent report to clinicians suggest that these results should be viewed as more preliminary.