Background: Cancer-related cognitive impairment (CRCI) is prevalent and persistent among breast cancer survivors (BCS). 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. (Clinical Trials #: NCT02822573). Methods: Women ≥ 18 years of age, with a history of breast cancer who completed ≥ 4 cycles of cytotoxic chemotherapy 1 to 5 years prior to enrollment, self-reported CRCI, with evidence of a memory deficit on the Hopkins Verbal Learning Test were eligible. Women were randomized to a 24-week course of daily donepezil (5mg) or placebo. If tolerated, the donepezil/placebo oral daily dose was increased to two tablets (donepezil 10mg) Weeks 7-24. The Functional Assessment of Cancer Therapy–Cognitive Function (FACT-Cog) Version 3 patient-reported outcomes (PRO) measure was administered at Baseline and weeks 12, 24, and 36. Mixed effects repeated measures analysis of covariance (RMANCOVA) models were used to assess treatment differences in FACT-Cog subscale scores 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 of 276 patients from 87 NCORP sites (mean age = 57.1 yr., SD = 10.5) an average of 29.6 months post-chemotherapy completion were randomized to donepezil (n = 140) or placebo (n = 136). Participants in both arms experienced an improvement in all FACT-Cog subscale scores from baseline to week 12 (e.g., FACT-Cog Perceived Cognitive Impairment change: Donepezil = 14.8, SD = 14.6; Placebo = 13.9, SD = 15.7), with a slight improvement in week 24 (Donepezil = 3.6, SD = 11.4; Placebo = 3.1, SD = 11.4) and slight decrease in week 36 (Donepezil = -1.7, SD = 12.4; Placebo = -1.2, SD = 12.2). The magnitude of change was comparable across treatments at all timepoints (week 12 p= 0.64; week 24 p= 0.75; week 36 p= 0.76). There were no statistically significant differences across treatments at 12, 24 and 36 weeks on any FACT-Cog subscale. Exploratory analyses 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 group differences for any outcome. Conclusions: There were no differences in PRO-assessed cognitive function domains between donepezil or placebo. The magnitude of improvement in patient-rated cognitive function was comparable across treatment arms. These results underscore the importance of placebo controls for CRCI intervention trials. Funding: NIH/NCI 2UG1CA189824. Clinical trial information: NCT02822573.