Background: We are conducting an exploratory, prospective study to investigate factors associated with radiation-induced fatigue in women with early breast cancer undergoing radiation therapy (RT) for breast conservation. Our hypothesis is that fatigue associated with adjuvant RT is related to tissue damage by apoptosis and inflammation, and to baseline psychological profiles. Methods: All subjects were assessed immediately before RT (T1), mid-point of RT (T2), end of RT (T3), 6 months (T4) and 1 year (T5) after completing RT. Clinical evaluations of skin toxicity, laboratory measures, fatigue, distress, depression, anxiety, sleep, energy and pain were assessed using validated measures. Results: Thirty-one subjects (target 50) have been enrolled to date; 23 have completed T3 and are presented here. 35% had a history of depression and 17% are currently depressed; 22% had past and current anxiety. BCTOS breast pain, tenderness and sensitivity increased during RT and were consistent with functional pain scores. No clinically relevant changes in energy or distress were seen. Despite a notable prevalence of depression and anxiety at baseline, there were no relevant changes in depression or anxiety. Most IL-1β, IL-4, IL-6 and IL-10 levels were undetectable. 39% of subjects showed increases in fatigue and were 14 years younger than non-fatigued subjects. Fatigued subjects had more frequent past (44%) and current (33%) depression than non-fatigued subjects (29% and 7%, respectively), and woke up tired more frequently (44% versus 0%). Current depression, but not fatigue, was associated with decreased a.m. cortisol levels during RT. 56% of fatigued subjects had an RTOG Acute Skin Toxicity score > 1 and 78% had BCTOS breast-specific pain subscales scores ≥ 3 during RT vs. 21% and 14% of non-fatigued subjects, respectively. Serum caspase-1 (inflammation) and caspase-3 (apoptosis), hs-CRP and TNF-α were increased but not associated with fatigue. Conclusions: Our preliminary findings suggest that radiation-associated fatigue is complex and, as hypothesized, is dependent on a patient’s psychological profile in the setting of skin toxicity and insomnia. If this data holds at study completion, it may guide clinical interventions.