Tau accumulation in patients with Alzheimer's disease tracks closely with cognitive decline and plays a role in the later stages of disease progression. This phase 2 study evaluated the safety and efficacy of tilavonemab, an anti-tau monoclonal antibody, in patients with early Alzheimer's disease. In this 96-week, randomized, double-blind, placebo-controlled study (NCT02880956), patients aged 55-85 years meeting clinical criteria for early Alzheimer's disease with a Clinical Dementia Rating-Global Score of 0.5, a Mini-Mental State Examination score of 22 to 30, a Repeatable Battery for the Assessment of Neuropsychological Status-Delayed Memory Index score of ≤85, and a positive amyloid PET scan were randomized 1:1:1:1 to receive one of three doses of tilavonemab (300 mg, 1000 mg, or 2000 mg) or placebo via intravenous infusion every 4 weeks. The primary end point was the change from baseline up to Week 96 in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Safety evaluations included adverse event monitoring and MRI assessments. A total of 453 patients were randomized, of whom 337 were treated with tilavonemab (300 mg, n = 108; 1000 mg, n = 116; 2000 mg, n = 113) and 116 received placebo. Baseline demographics and disease characteristics were comparable across groups. The mean age was 71.3 (SD 7.0) years, 51.7% were female, and 96.5% were White. At baseline, the mean CDR-SB score was 3.0 (1.2), which worsened through Week 96 for all treatment groups. The least squares mean change from baseline at Week 96 in the CDR-SB score with tilavonemab was not significantly different compared with placebo [300 mg (n = 85): -0.07 (95% confidence interval, CI: -0.83 to 0.69); 1000 mg (n = 91): -0.06 (95% CI: -0.81 to 0.68); 2000 mg (n = 81): 0.16 (95% CI: -0.60 to 0.93); all P ≥ 0.05]. The incidence of any adverse event and MRI findings were generally comparable across groups. Tilavonemab was generally well tolerated but did not demonstrate efficacy in treating patients with early Alzheimer's disease. Further investigations of tilavonemab in early Alzheimer's disease are not warranted.