BACKGROUND There is accumulating evidence indicating that inflammation and oxidative stress are involved in the pathogenesis of atrial fibrillation (AF). The role of manganese superoxide dismutase (MnSOD) in the initiation and maintenance of AF has not yet been well characterized. The aim of our study is to investigate whether or not plasma MnSOD levels are associated with AF. METHODS We enrolled a total of 130 consecutive patients with AF as the case group (paroxysmal AF: 87, persistent AF: 43) and 58 patients without a history of AF as the control group after screening. Baseline clinical characteristics, laboratory and echocardiographic parameters were collected. Plasma levels of nicotinamide-adenine dinucleotide phosphate oxidase 4 (NOX4) and MnSOD were measured by an enzyme-linked immunosorbent assay (ELISA) method. These data were compared between the different groups. The relationship between MnSOD and other parameters was assessed using Spearman correlation. Multivariable logistic regression analysis was performed to identify independent predictors of AF. The area under the curve (AUC) from receiver operating characteristics (ROC) analysis was constructed to explore the value of MnSOD in predicting the occurrence of AF. RESULTS The levels of MnSOD were the highest in the paroxysmal AF group, followed by the persistent AF group, and the lowest in the controls. Meanwhile, the levels in the paroxysmal AF group were significantly higher than those in the controls [322.84 (165.46, 547.61) vs. 201.83 (129.53, 301.93), p = 0.002], but no significant difference was found between the paroxysmal AF group and persistent AF group, as well as the persistent AF group and the controls. Spearman correlation analysis indicated that there was a significantly negative correlation between MnSOD levels and LAD (r = -0.232, p = 0.008) and a positive correlation between MnSOD levels and RDW-CV (r = 0.214, p = 0.014) in the case group. Multivariate logistic regression analysis indicated that MnSOD levels [odds ratio (OR): 1.003, 95% confidence interval (CI): 1.001-1.005, p = 0.002] were an independent risk factor for paroxysmal AF, and the best cut-off value of MnSOD in predicting paroxysmal AF gained by ROC curve analysis was 311.49 ug/mL (sensitivity of 52.9%, specificity of 77.6%, AUC = 0.668). CONCLUSIONS Oxidative stress underlies the pathogenesis of AF and may play a stronger role in paroxysmal AF than persistent AF. Our study showed an independent association between increased circulating plasma MnSOD levels and the occurrence of paroxysmal AF.