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.