Objective: To investigate the efficacy and safety of rivaroxaban versus warfarin in perioperative anticoagulation of radiofrequency ablation of atrial fibrillation. Methods: A total of 80 patients with atrial fibrillation undergoing radiofrequency ablation in Lu’an Shili Hospital from June 2017 to June 2020 were selected and randomly divided into 2 groups, 40 cases in each group. The control group was given warfarin anticoagulant therapy during perioperative period, and the observation group was given rivaroxaban anticoagulant therapy. The coagulation function [international normalized ratio (INR), fibrinogen (FIB), prothrombin time (PT), activated partial thromboplastin time (aPTT)], inflammatory factors [high-sensitivity C-reactive protein (hs-CRP), homocysteine (Hcy)] before the treatment, 1 month and 3 months after the operation were compared between the 2 groups. The incidences of thromboembolism and bleeding events in the 2 groups at 3 months after the operation were compared. Results: At 1 month and 3 months after the operation, PT and aPTT in the observation group were significantly higher than those in the control group (all P<0.05), FIB and serum hs-CRP and Hcy levels were significantly lower than those in the control group (all P<0.05). At 3 months after the operation, there was no difference in the incidence of thromboembolism between the 2 groups (P>0.05), and the incidence of bleeding events of the observation group was significantly lower than that of the control group (P<0.05). Conclusion: Compared with warfarin, rivaroxaban can enhance anticoagulant effect and reduce bleeding risk during radiofrequency ablation of atrial fibrillation.