© 2019, © 2019 Taylor & Francis Group, LLC. Purpose: Many clinical interventions have been designed to improve psychological well-being in women with breast cancer; however, there are individual differences in the extent of benefit across participants. Mindfulness-Based Stress Reduction (MBSR) is a structured 8-week intervention that has been shown to reduce depression and anxiety for patients with breast cancer. Personality factors may influence which participants benefit more from various psychological interventions, including MBSR. Design: In a secondary analysis, we examined whether personality factors accounted for variability in response to an MBSR intervention for women with breast cancer. Sample: Two hundred eighty Danish women with breast cancer who completed the Mindfulness and Cancer Mamma trial were included in this analysis. Methods: Using multiple regression analyses, we investigated whether personality factors, measured by the NEO-PI-R, contribute independently or interact with treatment to predict depressive symptoms at 2, 6, and 12-month follow-up. Findings: The interaction between low conscientiousness and MBSR, as well as high neuroticism and MBSR each predicted significantly lower levels of distress at 12-month follow-up compared to women who higher in conscientious or lower in neuroticism. Conclusions: Personality factors may contribute to the impact of psychosocial interventions, such as MBSR, on psychological well-being. Implications for Psychosocial Providers: Utilizing personality measures may assist providers in identifying which patients may benefit from mindfulness therapies.