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This randomized controlled trial (NCT04786496) examined the effects of a preventive intervention based on Incremental Theory of the Personality (ITP) on psychophysiological responses to social stress and evaluated whether levels of depression moderate the intervention effects. The participants, 107 first-year university students, were randomly assigned to one of three conditions: ITP intervention, ITP + a self-affirmation intervention (SA), and a control condition (CC). Indicators of the Hypothalamic–Pituitary–Adrenal axis, autonomic nervous system, and subjective mood were assessed with the Trier Social Stress Task. Participants in the ITP condition displayed a lower decline in respiratory sinus arrythmia (RSA) compared to those in the CC during the first phases of the task [Slopes: -0.08 (0.09) vs -0.21 (0.09), z = 2.86, p =.004] and a higher decrease in cortisol at recovery [β = -0.18 (0.08), z = -2.37, p =.018]. Depressive symptoms moderated the effect of ITP [β = -0.10 (0.05), z = -2.15, p =.032] and ITP+SA [β = -0.09 (0.04), z = -2.06, p =.039] in the decline during stress and recovery in RSA. In participants with low/medium levels of depressive symptoms, both interventions predicted a lower decline during stress [Slopes: -0.06 (0.09) for ITP, -0.17 (.09) for ITP+SA, and -0.26 (0.09) for CC] and higher recovery in RSA [Slopes: 0.18 (0.01) for ITP, 0.24 (0.01) for ITP+SA, and 0.30 (0.01) for CC]. The findings suggest that the ITP intervention has the potential to be an effective preventive intervention to reduce the stress response. [ABSTRACT FROM AUTHOR]