Background Individuals with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) have high plasma total homocysteine (tHcy) levels, which may be a risk factor for cognitive impairment. Whether treatment with high-dose B vitamins to decrease high tHcy levels improves cognition in persons with kidney disease is unknown. Study Design Randomized controlled trial. Setting & Participants A substudy of 659 patients (mean age, 67.3 ± 11.7 years) who participated in a randomized double-blind clinical trial 5 years in duration conducted in 36 US Department of Veterans Affairs medical centers of the effect on all-cause mortality of vitamin-induced lowering of plasma tHcy level. 236 (35.8%) were treated by using dialysis (ESRD) and 423 (64.2%) had a Cockcroft-Gault estimated creatinine clearance of 30 mL/min or less (advanced CKD). All had high tHcy levels (≥15 μmol/L) at baseline. Cognitive assessments began during the follow-up period of the main trial 3 years after treatment began; participants subsequently were retested 1 year later to assess cognitive change. Intervention Daily high-dose B vitamin capsule (40 mg of folic acid, 100 mg of vitamin B6 , and 2 mg of vitamin B12 ) or placebo. Outcomes Cognitive function at initial assessment and 1 year later. Measurements Telephone Interview of Cognitive Status–modified, supplemented with attention, working memory, and executive function tests. Results Initial cognitive function was impaired in approximately 19% of patients regardless of treatment assignment (vitamin or placebo) or kidney disease status (advanced CKD or ESRD). Treatment decreased tHcy levels by 26.7%. Unadjusted and adjusted analyses showed that treatment did not improve initial cognitive outcomes or affect subsequent cognitive status 1 year later. Limitations Cognitive assessments began after treatment was initiated; cognitive assessment was limited. Conclusion Treatment with high daily doses of B vitamins, which decreased tHcy levels, did not affect cognitive outcomes in patients with advanced CKD and ESRD.