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This pilot study examined whether breast cancer patients with childhood trauma exhibit increased fatigue, depression, and stress in association with inflammation as a result of whole breast radiotherapy (RT).Twenty breast cancer patients were enrolled in a prospective, longitudinal study of fatigue, depression, and perceived stress prior to RT, week 6 of RT, and 6 weeks post-RT. Six weeks after RT, subjects completed the childhood trauma questionnaire (CTQ). Patients were also administered the multidimensional fatigue inventory, inventory of depressive symptomatology-self-reported, and perceived stress scale at all three time-points and underwent blood sampling prior to RT for gene expression and inflammatory markers previously associated with childhood trauma and behavioral symptoms in breast cancer patients.Eight subjects (40%) had past childhood trauma (CTQ+). Compared to CTQ− patients, CTQ+ patients had significantly higher fatigue, depression, and stress scores before, during, and after RT (p< 0.05); however, RT did not increase these symptoms in either group. CTQ+ patients also exhibited increased baseline expression of gene transcripts related to inflammatory signaling, and baseline inflammatory markers includingc-reactive protein, interleukin (IL)-6, and IL-1 receptor antagonist were positively correlated with depression, fatigue, and stress scores in CTQ+ but not CTQ− patients.Childhood trauma was prevalent and was associated with increased symptoms of fatigue, depression, and stress irrespective of RT. Increased symptoms in CTQ+ patients were also associated with baseline inflammatory markers. Treatments targeting childhood trauma and related inflammation may improve symptoms in breast cancer patients. Copyright © 2015 John Wiley & Sons, Ltd.