Background <p>Current knowledge on whether chronic pain contributes to atrial fibrillation (AF) risk, especially under varying genetic susceptibilities, is limited. This study aimed to explore the association between chronic pain and AF risk and assess the combined impact of chronic pain and genetic susceptibility to AF, as defined by polygenic risk scores (PRS), in the UK Biobank cohort.</p> Methods <p>We analyzed data from 290,345 UK Biobank participants who were initially AF-free. Based on pain duration and location, participants were categorized into four groups: no pain, short-term pain, chronic localized pain, and chronic widespread pain (CWP). Genetic susceptibility to AF was quantified using PRS, categorizing individuals into low, intermediate, and high genetic risk groups. Cox proportional hazard regression analyses were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for assessing the risk of AF about chronic pain and genetic susceptibility.</p> Results <p>Over a median follow-up of 14.2 years, 19,998 participants (6.9%) developed AF. All pain categories were associated with a statistically significant increased risk of AF compared with the no pain category. Both chronic pain and higher PRS were independently associated with incident AF. Joint analyses revealed that, in the high genetic risk group, individuals with chronic localized pain and CWP had HRs of 3.52 (95% CI: 3.25–3.81) and 3.32 (95% CI: 2.71–4.08), respectively, compared to the low genetic risk and no pain group.</p> Conclusions <p>Chronic pain and PRS were independently associated with an increased risk of AF, and individuals with combined exposures had the highest risk.</p> Graphical Abstract <p></p>