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Objective: Elevated cancer antigen 125 (CA-125) levels are associated with cardiopulmonary disorders such as acute and chronic heart failure (HF), coronary artery disease, chronic obstructive pulmonary disease, and atrial fibrillation (AF). The development of atrial fibrillation (AF) is related to morbidity and mortality in patients with HF: therefore, it is important to identify patients with increased risk for development of AF. We investigated whether plasma CA-125 levels in patients with hospitalized systolic HF could predict the development of AF., Patients and Methods: A total of 149 consecutive patients with sinus rhythm who were admitted to the emergency department with hospitalized systolic HF were evaluated prospectively. Serum CA-125 levels were obtained after initial stabilization during their hospital stay., Results: AF developed in 36 (% 24.2) patients during a follow-up period of 22.1 ± 11  months (range 3-61). CA-125 levels were significantly higher in patients who developed AF than in patients with sinus rhythm [99 U/ml (48-172) vs. 47 U/ml (18-108), p = 0.001]. The optimal cut-off level of CA-125 to predict development of AF was found to be > 68.49 U/ml. CA-125 > 68.49 U/ml, left atrial diameter, right ventricular dilatation, moderate to severe mitral and tricuspid regurgitations were found to have prognostic significance in univariate analysis. In a multivariate Cox proportional hazards model with the backward stepwise method, CA-125 > 68.49 U/ml (HR = 2.693, % 95 CI = 1.285-5.641, p = 0.009) and moderate to severe mitral regurgitation (HR = 2.708, % 95 CI = 1.295-5.663, p = 0.008) were associated with an increased risk of new-onset AF after adjustment for variables found to be statistically significant in univariate analysis and correlated with CA-125 level., Conclusion: CA-125 level is associated with the development of AF in patients with hospitalized systolic HF.