Background: Promoting individual resilience – i.e., maintaining or regaining mental health despite stressful circumstances – is often regarded as important endeavor to prevent mental illness. However, digital resilience interventions designed to enhance mental health outcomes, including stress levels and self-perceived resilience, have yielded mixed results. Such heterogeneous effects reflect a variety of unsolved conceptual challenges in interventional resilience research. These range from grounding interventions in genuine resilience frameworks, using theory or targeting etiologically important resilience factors as intervention content, to a lack of knowledge about the mechanisms underlying effects, and employing techniques specifically developed to foster psychosocial resources. The web- and app-based resilience intervention RESIST was designed to address these challenges, mainly by utilizing both the Positive Appraisal Style Theory of Resilience as its theoretical foundation and interventional techniques from Strengths-based Cognitive Behavioral Therapy. Objective: The study’s primary aim was to evaluate the effectiveness of RESIST in a general working population as a means of universal prevention, relative to a waitlist control group. A secondary study aim was to explore the resilience factors of self-efficacy, optimism, perceived social support, and self-compassion the intervention targets as potential mediators of its effect on stress and self-perceived resilience. Methods: In total, 352 employees were randomly assigned to either a self-help version of RESIST or waitlist control group. Data were collected at baseline, post-intervention, and at 3- and 6-month (intervention group only) follow-up. The primary outcome was perceived stress, measured with the Perceived Stress Scale-10. Secondary outcomes included self-perceived resilience, the resilience factors targeted, and other mental and work-related health outcomes. Results: The intervention group reported significantly less stress than controls post-intervention (Δ=-3.14; d=-0.54, 95%CI -0.75 to -0.34, and P<.001 and at follow-up d="-0.47," to p=".002)." these improvements in the intervention group were maintained follow-up. favorable between-group differences also detected for self-perceived resilience factors. effects on other mental work-related outcomes mixed. parallel mediation analyses revealed significant indirect of optimism ci self-compassion perceived stress whereas through self-efficacy social support not found. a similar pattern emerged as outcome. conclusions: sample employees experiencing heightened work-burden levels resist was effective reducing increasing well targeted suggested that developing positive future outlook self-compassionate attitude toward oneself may be key drivers enhance resilience. changing quality relationships strengthening belief one abilities require more time involvement others or personal from health professional such an e-coach ensure sufficient learning opportunities. clinical trial: german trials register drks00017605 https:>