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Background: Vulvodynia is a chronic pain syndrome characterized by persistent vulvar pain, occurring without clinically identifiable disorders. Central sensitization (CS) is suggested to play a role in the pathophysiology of vulvodynia, as for other nociplastic pain conditions., Aim: This study delves into the complex interplay between psychosocial factors and CS burden in women with vulvodynia, aiming to identify potential predictors (temperament, personality traits, childhood adverse events, defense mechanisms, and mental pain) and understand their impact on quality of life (QoL)., Methods: A cohort-based cross-sectional web survey of 357 women with vulvodynia., Outcomes: Outcomes included 8 self-report measures to assess the Central Sensitization Inventory (CSI) and psychological variables, including sensory processing sensitivity, traumatic experiences, personality traits, defense mechanisms, and mental pain., Results: Hierarchical multiple regression analyses were conducted in study 1, revealing that the following predicted higher CSI scores in women with vulvodynia: higher emotional overexcitability, decreased low sensory threshold, increased bodily threat experiences, elevated psychoticism, greater use of immature and neurotic defense mechanisms, and heightened mental pain. The final regression model identified the following as the strongest predictors of CS: low sensory threshold (β = 0.316), bodily threat experiences (β = 0.145), neurotic defenses (β = 0.210), and mental pain (β = 0.269). In study 2, the model presented interactions among these psychological factors in predicting CSI values explaining 48.9% of the variance in CS, 30.3% in psychological QoL, and 57.1% in physical QoL., Clinical Translation: This model opens discussion for tailored psychological interventions aimed to improve overall QoL in women with vulvodynia., Strengths and Limitations: Strengths of the study include innovative insights into the interplay between psychological variables and the construct of CS and quality of life. As a limitation, the research was conducted as a cross-sectional study with self-reported measures., Conclusion: The study calls for comprehensive assessments that consider physical and mental aspects, paving the way for holistic health care approaches in the management of vulvodynia., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)