There is evidence that altering stress mindset — the belief that stress is enhancing vs. debilitating — can change cognitive, affective and physiological responses to stress. However, individual differences in responsiveness to stress mindset manipulations have not been explored. Given the previously established role of catecholamines in both placebo effects and stress, we hypothesized that genetic variation in catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, would moderate responses to an intervention intended to alter participants' mindsets about stress. Participants (N = 107) were exposed to a stress mindset manipulation (videos highlighting either the enhancing or debilitating effects of stress) prior to engaging in a Trier Social Stress task and subsequent cognitive tasks. The associations of the COMT rs4680 polymorphism with the effect of stress mindset video manipulations on cognitive and affective responses were examined. Genetic variation at rs4680 modified the effects of stress mindset on affective and cognitive responses to stress. Individuals homozygous for rs4680 low-activity allele (met/met) were responsive to the stress-is-enhancing mindset manipulation as indicated by greater increases in positive affect, improved cognitive functioning, and happiness bias in response to stress. Conversely, individuals homozygous for the high-activity allele (val/val) were not as responsive to the stress mindset manipulation. These results suggest that responses to stress mindset intervention may vary with COMT genotype. These findings contribute to the understanding of gene by environment interactions for mindset interventions and stress reactivity and therefore warrant further investigations.