Background: This RCT assessed the effect of 24 weeks of 5-10 mg per day of donepezil,an acetyl cholinesterase inhibitor,on cognitive functioning(primary endpoint)and fatigue,mood and QOL in long-term brain tumor survivors following partial or whole-brain irradiation.Cognitive results are reported herein.Methods: From 2/08-12/11,198 adult primary and metastatic brain tumor survivors.6 months post radiation treatment(.30 Gray)recruited at 24 sites affiliated with the Wake Forest Community Clinical Oncology Program Research Base,3 CTSU sites and M.D.Anderson Cancer Center were randomly assigned to receive donepezil(n599)or placebo(n599).Cognitive function was assessed at baseline,12 and 24 weeks with Hopkins Verbal Learning Test-Revised,Rey-Osterreith Complex Figure,Trail Making Test,Digit Span,Controlled Oral Word Association,and Grooved Pegboard.A Cognitive Composite(CC)score was the primary outcome.Results: The sample was 91%White,54%female,and median age was 55 yrs.66%had primary tumors,27%brain metastases and 8%PCI.Median time since diagnosis: 38 mos.95%had 0-1 ECOG performance status scores.74%completed the study.CC score improved significantly by 24 weeks in both arms(p,.01); however,there was not a statistically significant difference between groups(p 5.57).Donepezil group performed better than placebo on HVLT Recognition(p 5.03)and Discrimination(p 5.01)and GP-Dominant Hand(p 5 0.02).Significant interactions were found between treatment arm and baseline cognitive scores for: CC(p 5.01),HVLT Immed.Recall(p 5.03),HVLT%Savings(p,.01),Digit Span Forward(p 5.01),ROCF Copy(p 5.03),TMT-B(p 5.05)and GP-Dominant(p,.01).In all cases,the benefit of donepezil,relative to placebo,was greater for those with worse baseline scores.Conclusions: Long-term brain tumor survivors treated with brain irradiation who have cognitive impairment can benefit from 5-10mg of donepezil for 24 weeks.Improvements in verbal memory,working memory,visuo-and psychomotor performance and executive functioning were observed in this group.