Abstract Background Atrial fibrillation (AF) and hypertension (HTN) often occur together. A cross-sectional study in patients with AF has shown that blood pressure (BP) is associated with white matter lesions (WML), which are known to have a negative impact on cognitive function. Purpose We aimed to investigate the association of BP and new WML occurring in patients with AF during a follow-up of 2 years. Methods We enrolled 1129 patients with documented AF who underwent a standardized brain magnetic resonance imaging (bMRI) at baseline and after 2-years follow-up. Systolic and diastolic blood pressure (SBP and DBP) were measured at baseline in every patient. BP was categorized into the following groups: optimal BP (SBP <120 mmHg and DBP <80 mmHg); normal BP (SBP ≥120 and <130 mmHg or DBP ≥80 and <85 mmHg); high normal BP (SBP ≥130 and <140 mmHg or DBP ≥85 and <90 mmHg); HTN grade 1 (SBP ≥140 and <160 mmHg or DBP ≥90 and <100 mmHg); HTN grade 2 and 3 (SBP ≥160 or DBP ≥100 mmHg). We defined new WML as new lesions or preexisting lesions with an increased volume after a 2-year follow-up period. We performed logistic and linear regression analyses to examine the relationship of BP, BP categories and the presence and volume of new WML. Additionally, interaction analyses were performed to evaluate the potential modifying effect of AF type (paroxysmal vs. non-paroxysmal) and heart rhythm (AF/atrial flutter vs. sinus rhythm). Results The mean ± standard deviation age was 71.5 ±8.4 years, 909 (74%) patients were male, and the mean BP was 135/79 ±18/12 mmHg. At baseline, WML were present in 98.9% of patients, with a median (interquartile range) volume of 3362 (1241 – 8650) mm³. The overall prevalence of new WML after 2 years was 18.8%, with a median volume of 108 (46.5 – 264) mm³. The prevalence of new WML stratified by BP categories is presented in Figure 1. After adjusting for multiple covariates, the presence of new WML was not significantly associated with BP categories or continuous SBP (Table 1). Compared to patients with optimal BP, the adjusted odds ratios (OR) (95% Confidence Intervals) were 1.40 (0.86 to 2.29) for normal BP; 1.13 (0.69 to 1.85) for high normal BP; 1.09 (0.69 to 1.76) for HTN grade 1; and 1.20 (0.67 to 2.11) for HTN grade 2 and 3 (p for linear trend 0.86). Per 10 mmHg increase in SBP, the adjusted OR was 0.97 (0.89 to 1.05, p= 0.46). Similarly, BP was not associated with volume of new WML. AF type and heart rhythm did not show any significant interaction effect for the association between SBP and presence of new WML (p-value for interaction of p=0.16 and p=0.57, respectively). Conclusions In a large cohort of AF patients, we found no association between BP and the presence and volume of new WML after a follow-up of 2 years. Long-term follow-up is warranted to determine the impact of BP on the development of new WML over time.