Previous studies have documented the serotonin transporter linked polymorphic region (5-HTTLPR) as a genetic susceptibility variant that contributes to variability in outcomes related to affective psychopathology, with the short allele associated with negative affectivity and the long allele associated with positive affectivity. In a separate but related line of research, extensive evidence suggests that frontal electroencephalography (EEG) hemispheric asymmetry in the alpha band is also associated with risk for affective psychopathologies, with leftward asymmetry associated with approach-related behavior patterns and rightward frontal EEG asymmetry associated with withdrawn behavioral tendencies. We examined frontal EEG hemispheric asymmetries in relation to 5-HTTLPR genotyping in 70 children between 4 and 6 years of age. Analyses revealed that frontal EEG lateralization interacted with genotype such that children homozygous for the short allele exhibited rightward frontal EEG asymmetries, children who were homozygous for the long allele consistently exhibited a positive pattern of leftward asymmetry, and heterozygotes exhibited equivalent left and right frontal activity. These findings suggest that the 5-HTTLPR short allele may provide a degree of susceptibility for later affective psychopathology in adolescence and adulthood, through mediation of frontal brain activity that is associated with cognitive-behavioral withdrawal tendencies and negative affectivity.