Background: Neurobehavioral outcomes, such as fatigue and neurocognitive dysfunction, are disabling side effects in a subgroup of breast cancer (BC) patients. Longitudinal studies with appropriate controls to dissociate treatment-related effects from those experienced by healthy post-menopausal women are sparse, and virtually all define “pre-treatment” baseline as prior to adjuvant therapy, but following surgery. Given the phenomenon of “postoperative cognitive dysfunction” reported in older patients undergoing major surgery, we are evaluating treatment-related impact using pre-surgery assessment as the baseline. Methods: Eligible post-menopausal BC patients are assessed prior to any local or systemic treatment and one month after completion of treatment (surgery, radiation and/or chemotherapy). Healthy controls (HC) are age-matched 1:2-3 and tested at similar time intervals. Currently 130 BC and 60 HC are enrolled; results for 80 BC and 30 HC who have reached Time 2 are available (Mean time between assessments = 143 days, SD = 93). Results: Interim analyses using repeated measures ANOVA, controlling for age and education differences, show that the BC group declined in verbal memory functioning post-treatment relative to baseline, while the HC group improved due to practice effects (F(1, 102) = 3.43, p = .061). A similar interaction effect is observed for executive functioning, where the BC group failed to benefit from practice effects to the same degree as did HC (F(1, 102) = 6.04, p = .016). Anxiety but not depression was significantly elevated at baseline and decreased post treatment in BC patients treated with and without chemotherapy (F (1, 102) = 6.85, p = .010). Fatigue did not significantly change for the BC group; however, it was significantly higher than HC at baseline (t =2.77, p = .01) and remained high at the post-treatment measurement. Conclusions: Significant declines in neurocognitive functioning soon after completion of BC treatment were observed compared to healthy post-menopausal women. This observation did not appear to be due to mood disturbance, as anxiety and depression decreased following treatment. Our data also suggest that fatigue is present even prior to any cancer treatment.