Objective Ischemic stroke is a severe complication following cardiac surgery, but its risk factors remain unclear and need further study. This study assessed the predictive value of CHADS2 scores for perioperative ischemic stroke among atrial fibrillation (AF) patients undergoing mitral valve replacement surgery. Methods A total of 805 AF patients, with females accounting for 524% and at a mean age of (53.7±10.5) years, undergoing mitral valve replacement in our hospital from January 2005 to December 2014 were recruited in this study. Their CHADS2 scores were used to stratify the risk for perioperative stroke. The incidence of stroke during hospitalization was observed and compared between those with the score ≥2 and the score＜2. Multivariate logistic regression analysis was performed to determine the risk fcrtors used to predict stroke. The correlation of the score with perioperative stroke was analyzed. Results The CHADS2 scores were as follows in the subjects: 0 point in 493 cases (61.2%), 1 point in 185 cases (23.0%), 2 points in 92 cases (11.4%), 3 points in 26 cases (3.2%) and 4 points in 9 cases (1.1%). There were 14 patients (1.7%) having stroke and 16 (2.0%) dying during hospital stay. Stroke occurred in 6 cases in the 0-point patients (1.2%), 2 cases in the 1-point patients (1.1%), 3 cases in the 2-point patients (3.3%), 2 cases in the 3-point patients (77%), and 1 case in the 4-point patients (111%). Compared with the patients with CHADS2 score <2, those with the score ≥2 had higher incidence of stroke duringhospitalization (47% vs 12%, P=0005). The patients with higher CHADS2 score had higher proportions of being complicated with carotid artery stenosis, undergoing coronary artery bypass grafting (CABG) simultaneously, receiving mechanical valve replacement, and taking longer mechanical ventilation time post-operatively when compared with those with lower score (P<0.05). But there were no differences in the ICU stay length and intra-hospital mortality between them (P>0.05). Multivariate logistic regression analysis showed that the CHADS2 score ≥2 (OR=4.164, 95%CI: 1.388-12.495; P=0.011) and application of recombinant human coagulation factor Ⅶa (OR=11.757, 95%CI: 2.909-47.520; P=0.001) were independent risk factors for stroke during hospitalization. Conclusion There is an increased risk for stroke in the AF patients with higher CHADS2 score after mitral valve replacement. CHADS2 score ≥2 is an independent risk factor for stroke during hospitalization. The score is of significant value in the prediction of perioperative ischemic stroke in the AF patients undergoing mitral valve replacement surgery and worth further study.