<p>Cognitive Bias Modification – Interpretation (CBM-I) aims to alter maladaptive interpretations in social anxiety, yet effects are often small and outcome measures are diverse. Although CBM-I has shown promise, its underlying mechanisms remain unclear and integration with psychophysiological and neural measures has been limited. In this randomized controlled trial, eighty-eight participants with high levels of social anxiety completed two lab sessions, an online training in between, and online follow-up. Participants filled out questionnaires, completed interpretation bias tasks, and underwent neuro-psychophysiological assessments. Active CBM-I trained positive resolutions of ambiguous social scenarios, while the sham version used neutral scenarios. The primary outcome, i.e., scores on the Liebowitz Social Anxiety Scale (LSAS), decreased across time in both groups, without group differences. However, the Brief Fear of Negative Evaluation decreased only in the active group. Interpretation bias shifted more strongly toward positive outcomes in the active group. Autonomic measures confirmed sensitivity to stress induction but did not differentiate between conditions. Electrophysiological results paralleled subjective ratings, as participants exhibited ambivalent responses to socially relevant stimuli but clearly differentiated responses toward neutral stimuli. Baseline correlations indicated strong convergence across self-report and interpretation tasks. Mediation analyses showed that reductions in negative interpretations mediated the effect of the training group on LSAS scores at follow-up. These findings identify interpretation bias as a modifiable mechanism underlying social anxiety and underscore its role as a transdiagnostic marker. Targeting interpretation bias through easily accessible and applicable online interventions may strengthen preventive and therapeutic approaches for social anxiety and related disorders.</p>