Objectives: To examine the association between single nucleotide polymorphisms (SNPs) near PITX2 and left atrial size in patients with atrial fibrillation (AF). Background: Recent studies have shown that several genetic variants near the PITX2 locus on chromosome 4q25 are associated with AF. However, the mechanism that mediates this association remains unclear. Basic murine studies suggest that reduced PITX2 expression is associated with left atrial dilatation. Methods: We prospectively enrolled 96 patients (mean age 60 ± 10 yrs, 72 % male) with drug resistant AF (57% paroxysmal, 38% persistent and 5% longstanding persistent) who underwent catheter ablation. Following DNA extraction from blood obtained pre-operatively, SNPs rs10033464 and rs2200733 were genotyped using the Sequenom MassARRAY. Left atrial volume (LAV) was determined using 3-dimensional imaging (CT or MRI prior to first ablation) by investigators blinded to genotype results. Results: The minor allele frequency at SNPs rs10033464 and rs2200733 were 0.14 and 0.25, respectively. Using multivariate linear regression, the minor allele at rs10033464 (co-dominant model) was independently associated with larger LAV (P = 0.037) after adjustment for age, gender, BMI, type of AF, left ventricular ejection fraction, and history of hypertension. However, no association was found between rs2200733 variant alleles and LAV (P = 0.82). Conclusion: SNP rs10033464 near the PITX2 locus on 4q25 is significantly associated with LAV. Left atrial dilatation may mediate the association of common variants at 4q25 with AF.