Background: There is a known strong genetic contribution to aggression in those with ADHD. In a previous investigation of a large population cohort, impaired ’emotional/social cognitive’ processing, assessed by questionnaire, was observed to mediate the link between COMT Val158Met and aggression in individuals with ADHD. We set out to replicate and extend this finding in a clinical sample, using task-based and physiological assessments of emotional and cognitive processing. Our aim was to test the hypothesis that directly assessed emotional processing mediates the link between COMT Val158Met and aggression in young people with ADHD. Methods: Males aged 10-17 years with ADHD were recruited from UK community clinics (n = 194). Research diagnostic interviews (parent and child) were used to assess psychopathology and generate DSM-IV Conduct Disorder symptom scores. Participants completed tasks assessing executive function (response inhibition and set shifting), empathy for fear, sadness and happiness, and fear conditioning [measured using skin conductance responses (SCR) to aversive stimuli]. Results: COMT Val allele carriers showed poorer response inhibition (F = 5.27, p = .02) and set shifting abilities (F = 6.45, p = .01), reduced fear empathy (F = 4.33, p = .04) and reduced autonomic responsiveness (lower SCRs) to the conditioned aversive stimulus (F = 11.74, p = .001). COMT Val158Met did not predict impairments in recognising others’ emotions or affective empathy for happiness or sadness. Mediation analysis revealed that impaired fear-related mechanisms indirectly mediated the link between COMT Val158Met and aggression. Conclusion: Our findings suggest fear mechanisms as possible targets for psychological interventions to disrupt links between genetic risk and aggressive outcomes in ADHD. Our findings also reveal the potential of hypothesis-driven approaches for identifying neuropsychological mechanisms that mediate genetic risk effects on behaviour and psychopathology.