Several lines of evidence support the role of monoaminergic and cholinergic dysregulation in attention deficit hyperactivity disorder (ADHD) and the concept that peripheral blood neurotransmission indices may represent valuable surrogate CNS markers. We determined platelet MAO-B activity (p-MAO-B) and lymphocyte muscarinic cholinergic receptor binding (l-MR) in 44 unmedicated ADHD children (aged 9.1 +/- 2.87 years) and in 26 age-matched controls for comparison. Lower levels of p-MAO-B (approximately 35%) and l-MR (approximately 55%) in ADHD were observed compared with controls. Differences were gender-dependent: p-MAO-B was reduced in males only (5.20 +/- 2.99 vs 8.46 +/- 5.1 nmol mg(-1) protein h(-1) in ADHD and controls, respectively) and l-MR in females only (ADHD vs control: 6.63 +/- 1.75 and 15.30 +/- 8.35 fmol 10(-6) cells). The clinical significance was corroborated by the correlation between these markers and severity of specific symptoms: lower p-MAO-B associated with increased inattention scores (Conners' teacher-rating scale); lower l-MR associated with increased score for oppositional-defiant disorder (ODD) (SNAP-IV); and trend towards correlation between increased inattention (SNAP-IV) and lower l-MR.