Emotional dysregulation is a core characteristic of many psychiatric diseases, including the anxiety disorders. Although heritable influences account for a significant degree of variation in risk for such disorders, relatively few candidate susceptibility factors have been identified. A coding variant in one such gene, encoding the dopamine catabolic enzyme catechol-O-methyltransferase (COMT Val158Met), has previously been associated with anxiety and with anxiety-related temperament and altered neural responses to affective stimuli in healthy individuals. In 96 healthy women recruited from a sample of 800 participants according to genotype, the authors tested for an association between the DRD2/ANKK1 Taq Ia, the COMT Val158Met, and a psychophysiological measure of emotion processing, the acoustic affective startle reflex modulation (ASRM) paradigm, and found that COMT genotype significantly affected startle reflex modulation by aversive stimuli, with Met158 homozygotes exhibiting a markedly potentiated startle reflex compared with Val158 carriers. A trait measure of anxiety (Gray's Behavioral Inhibition System; J. A. Gray & N. McNaughton, 2000) was also associated with ASRM. The functional polymorphism in the dopamine D2 receptor (DRD2/ANKK1 Taq Ia) had no effect on startle modulation. The findings support prior genetic and neuroimaging associations of the COMT 158Met allele to affective psychopathology and alterations in neural systems for emotional arousal and regulation.