In preclinical studies, the PKCε activator bryostatin-1 induces growth of mature synapses, prevents neuronal death, and influences amyloid plaques and tau tangles. We report the first safety and efficacy study of repeated doses of bryostatin in Alzheimer's disease (AD). Adults with moderate–severe AD (MMSE-2: 4–15 inclusive) received biweekly infusions of placebo or bryostatin-1 (20 or 40μg) for 12 weeks. Endpoints included the Severe Impairment Battery (SIB) and an Activities of Daily Living Inventory-Severe Impairment Version (ADCS-ADL-SIV) at baseline, weeks 5,9,13, and 30d after last infusion. Safety evaluations included routine blood tests and treatment emergent adverse events (TEAEs). A mixed-model for repeated measures was used to assess change from baseline to week 13 (Δ13) between each bryostatin group and placebo (1-tailed α=0.10 and power=80%) in predefined populations of the Full Analysis Set (≥1 post-baseline efficacy assessment) and Completer AnalysisSet (completed week 13 visit). Randomization was stratified by MMSE-2 4–9 vs. 10–15. Bryostatin-1 was provided by the National Cancer Institute. 147 adults were randomized in 28 centers with n=135 in the Full Analysis Set and n=113 in the Completer Analysis Set. Full Analysis Set mean(sd) age=71.6(7.9), MMSE-2=10.2(3.4), and 51.9% females with no imbalances among arms. 83.0% used acetylcholinesterase inhibitors, 67.4% memantine, and 58.5% both. The Δ13 (80%CI) in SIB was 1.9(-0.3,4.2) for 20μg and 0.8(-1.4,4.0) for 40μg in the Full Analysis Set, and this finding was strengthened when analyses were confined to the Completer Analysis Set (2.6 [0.4,4.9] for 20μg and 1.5[-0.7,3.8] for 40μg). Subjects who completed the 30d followup had sustained benefit. In the FAS, Δ13 for the ADCS-ADL-SIV was 1.4(0.0,2.8) for 20μg and 0.8 (-0.6,2.3) for 40μg group. TEAE rates were 58% in placebo, 65% in 20μg and 83% in the 40μg groups. TEAEs >placebo in both arms included diarrhea, while the 40μg arm also included fatigue, weight loss and myalgia. 20μg of bryostatin-1 every other week for 12 weeks appeared safe and benefited cognition and activities of daily living in moderate to severe AD. These results suggest acceptable safety and clinical benefits for the 20 μg group and support further development of bryostatin-1.