Objective Left atrial enlargement (LAE) may predispose individuals to blood stasis in atrial fibrillation (AF), and thus play a crucial role in thrombogenesis. The D-dimer level is one of the surrogate markers for a hypercoagulable state and reflects thrombus formation in AF. Since the D-dimer level reflects hypercoagulability as well as thrombus and fibrin burdens, LAE could be associated with a D-dimer elevation. However, no studies have explored this association or which factors contribute to increases in the D-dimer levels in patients with AF. Therefore, we assessed whether the serum D-dimer levels are related to the left atrial volume index (LAVI) or other vascular risk factors and also evaluated the association between the D-dimer levels and the initial stroke severity. Methods Ninety-eight consecutive patients with an acute ischemic stroke and non-valvular AF (NVAF) who were anticoagulation-naïve were enrolled, and all patients were stratified into moderate-to-severe and mild neurologic deficit groups using the National Institutes of Health Stroke Scale on admission. The association between the initial serum D-dimer levels and the LAVI was evaluated in all enrolled patients, and the serum D-dimer levels were compared between the two groups. Results The patients were classified into two groups according to the severity of the neurologic deficit. In a partial correlation coefficient analysis adjusted for confounding factors, an increase in the initial serum D-dimer levels was significantly associated with LAVI (r=0.286; p=0.027). A linear regression analysis showed that a history of peripheral artery disease was the factor most strongly associated with the serum D-dimer level (t=3.90, p<0.001), followed by LAVI (t=2.37, p=0.021) and a history of congestive heart failure (t=2.16, p=0.035). The D-dimer levels were higher in the moderate-to-severe neurologic deficit group than in the mild deficit group, but this difference was not statistically significant (4.5±7.1 vs. 1.6±2.6 mg/L, p=0.068). Conclusion The serum D-dimer levels were significantly associated with LAE in anticoagulation-naïve patients with an acute ischemic stroke and NVAF.