Background: Although P300 amplitude reductions constitute a persistent finding in children of addicted parents, relatively little is known about the specificity of this finding. The major aim of this study was to investigate the association between parental rearing, adverse life events, stress-reactivity, substance use and psychopathology on the one hand, and P300 amplitude in response to both target and novel distracter stimuli on the other hand. Moreover, we assessed whether risk group status (i.e., having a parental history of Substance Use Disorders [SUD]) uniquely contributed to P300 amplitude variation above and beyond these other variables. Methods: Event-related potentials were recorded in high-risk adolescents with a parental history of SUD (HR; n=80) and normal-risk controls (NR;n=100) while performing a visual Novelty Oddball paradigm. Stress-evoked cortisol levels were assessed and parenting, life adversities, substance use and psychopathology were examined by using self-reports. Results: HR adolescents displayed smaller P300 amplitudes in response to novel- and to target stimuli than NR controls, while the latter only approached significance. Interestingly, the effect of having a parental history of SUD on target-P300 disappeared when all other variables were taken into account. Externalizing problem behavior was a powerful predictor of target-P300. In contrast, risk group status uniquely predicted novelty-P300 amplitude reductions above and beyond all other factors. Conclusion: Overall, the present findings suggest that the P300 amplitude reduction to novel stimuli might be a more specific endophenotype for SUD than the target-P300 amplitude. This pattern of results underscores the importance of conducting multifactorial assessments when examining important cognitive processes in at-risk adolescents. © 2013 Euser et al.