Alzheimer’s disease is a chronic neurodegenerative disease with multiple pathogenesis pathways. Sildenafil, one of the phosphodiesterase-5 inhibitors, was proven to have effective benefits in transgenic Alzheimer’s disease mice. The purpose of the study was to investigate the relationship between sildenafil use and the risk of Alzheimer’s disease based on the IBM^® MarketScan^® Database covering over 30 million employees and family members per year. Sildenafil and non-sildenafil-matched cohorts were generated using propensity-score matching with the greedy nearest-neighbor algorithm. The propensity score stratified univariate analysis and the Cox regression model showed that sildenafil use was significantly associated with a 60% risk reduction of developing Alzheimer’s disease (HR=0.40; 95%CI:0.38-0.44; P<.0001) compared to the cohort of individuals who did not take sildenafil. Sex-stratified analyses revealed that sildenafil was related to a lower risk of Alzheimer’s disease in subgroups of both males and females. Our findings demonstrated a significant association between sildenafil use and a lower risk of Alzheimer’s disease.