Background: Cancer-related cognitive impairment (CRCI) is common among breast cancer survivors (BCS). Prior studies of late CRCI suggest repurposing cognitive enhancing medication may benefit survivors. The REMEMBER prospective, randomized, double-blind, placebo-controlled trial compared the efficacy of donepezil, an acetylcholine esterase inhibitor, versus placebo to reduce late CRCI among BCS previously exposed to chemotherapy. (Clinical Trials #NCT02822573). Methods: Women ≥ 18 years of age, with a history of breast cancer who completed ≥ 4 cycles of chemotherapy 1 to 5 years prior to enrollment, self-reported CRCI, with evidence of a memory deficit on the Hopkins Verbal Learning Test-Revised (HVLT-R) were eligible. Women were randomized to a 24-week course of donepezil (5mg/daily x 6 wk. titrated to 10mg/daily x 18 wk.) or placebo. A cognitive battery assessing memory, attention, executive function, verbal fluency, and processing speed was administered at baseline, week 12, 24 (end of intervention), and 36 (wash-out) along with patient-reported outcome measures and adverse events. There was 90% power to detect a treatment difference of 2 words for HVLT-IR (effect size=0.47) Mixed effects repeated measures analysis of covariance (RMANCOVA) models were utilized to assess treatment differences in memory (primary outcome) and other cognitive domains (secondary outcomes) with model covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification and an unstructured covariance matrix to account for within participant correlation over time. Results: A total of276 patients from 87 NCORP sites (mean age=57.1yr, SD=10.5) an average of 29.6 months post-chemotherapy completion were randomized to donepezil (n=140) or placebo (n=136). The primary outcome of memory (HVLT-R total) at 24 weeks was not different between treatments (donepezil mean=25.98, placebo = 26.50, p=0.32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks on attention, executive function, verbal fluency, or processing speed. Exploratory analyses additionally adjusting for education, baseline fatigue and depression as well as independent analyses considering treatment interaction with endocrine therapy and menopausal status also did not result in any differences by group for any outcomes. Twenty-five grade 3 or 4 adverse events were reported with no differences by treatment. Conclusions: BCS 1-5 years after completing chemotherapy, randomized to 24 weeks of a daily dose of 5-10mg of donepezil, did not perform differently at the end of treatment on tests of memory or other cognitive functions than survivors randomized to placebo. Funding: NIH/NCI 2UG1CA189824. Clinical trial information: NCT02822573.