AIMS: Atrial fibrillation (AF) is a prevalent clinical condition worldwide, with a high global incidence that significantly impacts disease burden and mortality rates. Single nucleotide polymorphisms in ABCB1 and ABCG2 are common, but the clinical outcomes are poorly understood. This study examines the association between the genetic variations of ABCB1 and ABCG2 and the risk of AF in a Taiwanese population. METHODS AND RESULTS: This case-control study recruited 216 AF patients from two hospitals in Taiwan between 2021 and 2023. Control groups were matched by age (± one year), gender, and AF-related variables from the Taiwan Biobank. Logistic regression analyzed the association between three genetic variants and AF risk. A significant association was noted between ABCG2 rs2231142 and AF risk. Those with ABCG2 rs2231142 G/T and T/T genotypes had a 1.91-fold (95 % CI = 1.04-3.53) increased risk of AF compared to those with the G/G genotype. This association was particularly pronounced in males in those carrying ABCG2 rs2231143 T/T genotype having a 4.47-fold (95 % CI = 1.02-19.67) increased risk after adjusting for covariates. There were no overall significant associations between AF risk and the polymorphisms of ABCB1 rs4148738 and rs1128503. CONCLUSION: A robust risk association between the ABCG2 rs2231142 T allele and AF in Asian populations, particularly in male adults, suggests that genetic testing for this polymorphism could be integrated into risk assessment models for AF.