Background The objective of this study was to investigate whether the NPY rs16147 polymorphism interacts with the environment to have an impact on resilience and positive future focus. Methods In Study 1, 1,140 earthquake survivors were evaluated; self-reported trauma exposure level and resilience were reported. Study 2 included 2,370 company employees and university students; information regarding self-reported early stressful life events and positive future focus were obtained. Results In both studies, the results showed a significant effect of interaction between the NPY rs16147 polymorphism and the level of stress on resilience. In Study 1, the T allele carriers reported consistent levels of resilience in low, moderate, and high levels of trauma exposure. In Study 2, the T genotype was associated with higher levels of positive future focus following early adversity. Conclusions Our findings are discussed in light of the differential post-stress growth hypothesis.