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Purpose Cognitive alterations are reported in breast cancer patients receiving chemotherapy. This has adverse effects on patients’ quality of life and function. This systematic review investigates the effectiveness of pharmacologic and non-pharmacologic interventions to manage cognitive alterations associated with breast cancer treatment. Methods Medline via EBSCOhost, CINAHL and Cochrane CENTRAL were searched for the period January 1999 to May 2014 for prospective randomized controlled trials related to the management of chemotherapy-associated cognitive alterations. Included studies investigated the management of chemotherapy-associated cognitive alterations and used subjective or objective measures in patients with breast cancer during or after chemotherapy. Two authors independently extracted data and assessed the risk of bias. Results Thirteen studies involving 1138 participants were included. Overall, the risk of bias for the 13 studies were either high (n=11) or unclear (n=2). Pharmacologic interventions included psychostimulants (n=4), epoetin alfa (n=1), and Ginkgo biloba (n=1). Non-pharmacologic interventions were cognitive training (n=5) and physical activity (n=2). Pharmacologic agents were ineffective except for self-reported cognitive function in an epoetin alfa study. Cognitive training interventions demonstrated benefits in self-reported cognitive function, memory, verbal function and language and orientation/attention. Physical activity interventions were effective in improving executive function and self-reported concentration. Conclusion Current evidence does not favor the pharmacologic management of cognitive alterations associated with breast cancer treatment. Cognitive training and physical activity interventions appear promising, but additional studies are required to establish their efficacy. Further research is needed to overcome methodological shortfalls such as heterogeneity in participant characteristics and non-standardized neuropsychological outcome measures.