Background : Women with breast cancer commonly experience fatigue and depressive symptoms before, during, and after treatment. Many studies have found that fatigue and depression are correlated in women with breast cancer throughout treatment, but there are few studies that have investigated the temporal nature of this relationship. Methods : As part of a larger study investigating sleep and fatigue in breast cancer, 89 women (mean age=51.9 yrs) with breast cancer were assessed for fatigue and depressive symptoms before beginning chemotherapy and in the last week of cycle 4 of chemotherapy. Fatigue was assessed using the Multidimensional Fatigue Scale - Short Form (MFSI-SF). Depressive symptoms were assessed with the Center for Epidemiological Studies-Depression (CES-D) questionnaire, and only women with a baseline CES-D score less than 16, suggestive of no depressive symptoms, were included in the study. The relationship between baseline MFSI-SF scores and the final CES-D scores was modeled with multiple regression models adjusted for demographic and disease related confounders. Results : The MFSI-SF mental subscale was the only fatigue measure to remain significantly associated with either the final CES-D score (B=0.156, p=0.002) or final CES-D score ≥16 (O.R.=1.20, 95% C.I.=1.01-1.42) after adjustment for baseline CES-D score, antidepressant use, and ethnicity in a multiple regression model. Conclusion : This study suggests that women with breast cancer who have higher levels of mental fatigue prior to chemotherapy are more likely to experience higher levels of depressive symptoms and progression to clinically significant depression following chemotherapy. Future studies should investigate if interventions that decrease fatigue prior to or early in cancer treatment will prevent worsening of depressive symptoms.