Importance: Multivariable comorbidity research indicates that childhood adversity increases the risk for the development of common mental disorders. This risk is explained by underlying internalizing and externalizing transdiagnostic constructs that are amplified by environmental stressors. The differential susceptibility model suggests that this interaction of risk and environment is bidirectional: at-risk individuals will have worse outcomes in high-stress environments but better outcomes in in low-stress environments. Objective: To test the differential susceptibility model by examining how a history of adverse childhood experiences moderates the association between life stress and transdiagnostic psychopathology. Design, Setting, and Participants: Data came from the US National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a population-based observational longitudinal survey administered to adults (≥18 years of age). Participants completed the survey at wave 1 (from 2001 through 2002) and wave 2 (from 2004 through 2005). Responses from 34 458 participants were used for the analyses from March 3, 2017, through October 8, 2018. Main Outcomes and Measures: Latent variables for internalizing-fear, internalizing-distress, externalizing, and general psychopathology were created to represent continuous levels of psychopathology in each wave. Latent variables were also created to represent continuous levels of life stress at each wave. Level of childhood adversity was characterized based on the number of types of childhood adversity experienced (no [0 types], low [1-2 types], and high [≥3 types] exposure). Analyses examined how the interaction between level of childhood adversity and adult life stress was associated with change in adult transdiagnostic psychopathology factors. Results: Of the 34 458 participants included in the analysis (58.0% women and 42.0% men; mean [SD] age, 46.0 [17.4] years at wave 1 and 49.0 [17.3] years at wave 2), 40.5% had no adverse childhood experiences, 34.6% had 1 to 2, and 24.9% had 3 or more. At wave 1, 61.5% of the sample endorsed at least 1 stressful life event and 27.2% met criteria for at least 1 mental disorder; at wave 2, these figures were 64.7% and 29.7%, respectively. Childhood adversity moderated the association between changes in adult life stress and changes in all transdiagnostic psychopathology factors. Specifically, higher levels of childhood adversity had a stronger association between adult life stress and adult transdiagnostic psychopathology factors. Further, significant differences between childhood adversity groups occurred in the mean scores of all transdiagnostic psychopathology factors for both increases and decreases in life stress, providing preliminary evidence of differential susceptibility. Conclusions and Relevance: Results provide empirical support for childhood adversity as a differential susceptibility factor engendering heightened functional and dysfunctional reactivity to later stress.