Objective: Evaluate the safety and efficacy of low-dose naproxen for prevention of progression in pre-symptomatic AD among cognitively intact persons at-risk. Methods: INTREPAD, a two-year double-masked pharmaco-prevention trial, enrolled 195 AD family history-positive elderly (mean age 63 years) screened carefully to exclude cognitive disorder. These were randomized 1:1 to naproxen sodium 220mg twice-daily or placebo. Multimodal imaging, neurosensory, cognitive and (in ~50%) CSF biomarker evaluations were performed at Baseline, 3, 12, and 24 months. A modified intent-to-treat analysis considered 160 participants who remained on-treatment through their first follow-up examination. The primary outcome was rate of change in a multimodal composite pre-symptomatic Alzheimer Progression Score (APS). Results: Safety: Naproxen-treated individuals showed a clear excess of adverse events. Efficacy: Among treatment groups combined, the APS increased by 0.101 points/year (S.E = 0.014; P < 10-5), but rate of change showed little difference by treatment assignment (0.017 points/year). The treatment-related slope ratio of 1.10 (95% Confidence Interval 0.588–2.04) suggested that naproxen does not reduce the rate of APS progression by more than 41%. Secondary analyses revealed no notable treatment effects on individual CSF, cognitive, or neurosensory biomarker indicators of progressive pre-symptomatic AD. Conclusions: In cognitively intact individuals at-risk, sustained treatment with naproxen sodium 220 mg twice-daily increases frequency of adverse health effects but does not reduce apparent progression of pre-symptomatic AD. Classification of Evidence: This study provides Class I evidence that, for people who are cognitively intact, low-dose naproxen does not significantly reduce progression of a composite indicator of pre-symptomatic AD.