Background The lipoprotein-associated phospholipase A2 inhibitor (Lp-PLA2), rilapladib (SB659032), is being evaluated as a potential treatment to slow the progression of Alzheimer's disease (AD). Methods One hundred twenty-four subjects with possible mild AD and with neuroimaging evidence of cerebrovascular disease were randomized to placebo or 250-mg rilapladib once daily, for 24 weeks, in addition to stable background acetylcholinesterase inhibitor and/or memantine. The study assessed the safety and tolerability of rilapladib and its effects on cognition, mechanistic, and disease-related biomarkers. Although the overall intent behind the study was to take a broad exploratory view of the data, two primary end points of interest (cerebrospinal fluid [CSF] amyloid beta peptide 1–42 [Aβ1–42] and CogState executive function/working memory [EF/WM] composite score at week 24) were prespecified in the analysis plan for inferential statistical analysis. Results Rilapladib was well tolerated with no significant safety concerns. A significant difference from placebo was observed for rilapladib on change from baseline in EF/WM (effect size, 0.45; P = .026). There was no significant difference between groups on the change from baseline in CSF Aβ1–42 (P = .133). Preliminary evidence of effects was detected on other mechanistic (albumin quotient) and disease-related biomarkers (tau/P-tau and neurofilament light chain). Conclusion These data provide initial evidence supporting Lp-PLA2 inhibition as a novel treatment for dementia. Clinical Trial Registration Clinicaltrials.gov identifier: NCT01428453.