Background: Breast cancer survivors report long term cognitive and quality of life effects due to cancer and chemotherapy. Cognitive enhancers (donepezil) could be a treatment option. We conducted a randomized, placebo-controlled phase II study to determine the feasibility of a larger phase III trial to improve cognitive function in breast cancer survivors with self-reported cognitive problems 1 to 5 years following chemotherapy. Methods: 62 patients were randomized to receive donepezil (5mg x 6 weeks + 10 mg x 18 weeks) or placebo. Participants completed a comprehensive battery of neurocognitive tests and questionnaires measuring cognitive symptoms, mood, fatigue, sleep disturbance and quality of life at baseline, 24, and 36 weeks post randomization. Women were screened for cognitive impairment with the FACT-Cog Perceived Cognitive Impairment subscale and were eligible if they scored <63. Results: The study opened at 16 sites and enrolled 62 women over 6 months (accrual rate of 10.2subjects/month). Ages ranged from 39 to 79 years (median of 56 years). 90% of the women were Caucasian, 87% were overweight or obese, and 65% had completed chemotherapy 1 and 3 years ago. Baseline FACT-PCI scores ranged from 5 to 61; 34 (55%) had scores < 30. Retention was 84% at 12 weeks and 76% at 24 weeks. Adherence to donepezil while on study ranged from 88% to 100%. Scores on the quality of life measures (SF-36, FACIT-Fatigue, PROMIS-7, Epworth Sleepiness Scale, Beck Depression Index and the Beck Anxiety Index) improved over the 24 weeks of treatment in both groups. In addition, scores for most of the neurocognitive tests improved over time in both arms. The study was not powered to detect differences in QOL or neurocognitive performance between arms, but positive trends in favor of Donepezil were noted for total recall and discrimination on the HVLT (Hopkins Verbal Learning Test) (p=0.08 and 0.02, respectively). Conclusions: In this cohort of breast cancer survivors reporting cognitive problems 1-5 years following chemotherapy, we had excellent accrual, retention and adherence. QOL and HVLT improved over 24 weeks. These data support a phase III trial of donepezil for the treatment of cognitive dysfunction in this population. Clinical trial information: NCT01466270.