To investigate the potential relationship between common nonsteroidal anti-inflammatory drugs (NSAIDs), genetic susceptibility and all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VD) among individuals experiencing chronic pain.This study was based on 194,758 chronic pain participants form UK biobank with a median follow-up of 13.7 years. Participants were categorized into different NSAIDs painkiller regimen groups: No NSAIDs group, Aspirin group, Ibuprofen group, Paracetamol group, and 2-3 NSAIDs group. Cox proportional risk models were used to examine the correlation between regular NSAIDs usage and the risk of ACD, AD, and VD. In addition, we further performed subgroup analyses and sensitivity analyses.1) Compared to the No NSAIDs group, the aspirin group (HR = 1.12, 95% CI:1.01-1.24, P < 0.05), the paracetamol group (HR = 1.15, 95% CI:1.05-1.27, P < 0.01), and the 2-3 NSAIDs group (HR = 1.2, 95% CI:1.08-1.33, P < 0.05) showed a higher risk of ACD. Furthermore, the 2-3 NSAIDs group was also associated with a higher risk of VD (HR = 1.39, 95% CI: 1.08-1.33, P < 0.05). 2) At high dementia GRS participants with chronic pain, the paracetamol group (HR = 1.2, 95% CI: 1.03-1.43, P < 0.05) and the NSAIDs group (HR = 1.3, 95% CI: 1.07-1.59, P < 0.05) were associated with a higher risk of ACD compared to the no painkiller group. 3) There was no significant association between ibuprofen use and higher risk of dementia.In individuals with chronic pain, the use of aspirin and paracetamol was associated with a higher risk of ACD, whereas the use of ibuprofen was not significantly associated with a higher risk of ACD.Copyright © 2023 Elsevier Ltd. All rights reserved.