Abstract Background Though early rhythm control (ERC) in patients with atrial fibrillation (AF) is effective in reducing stroke, the benefit of ERC has not been well-elucidated in cancer survivors. This study aimed to compare the risk of ischemic stroke between ERC and usual care in cancer survivors with AF and cancer. Methods This nationwide observational study was conducted using the Korean National Health Insurance Service database. Patients aged 20 years or older with newly diagnosed AF between 2009 and 2018 were included. Patients who received rhythm control therapy within 1-year of AF diagnosis were defined as the ERC group, while the remaining patients were defined as the usual care group. The risk of ischemic stroke in the ERC group compared to the usual care group was evaluated in long-term cancer survivors (cancer diagnosis ≥5 years) and the non-cancer group. Results A total of 591,692 patients were included in the study (18,747 patients [3.2 %] with cancer, mean age 65.7±14.6 years, 53.7% men, mean CHA2DS2-VASc score 3.3±2.0). The proportion of patients receiving ERC was slightly higher in cancer survivors compared to the non-cancer group (28.0% vs 25.3%, p<0.001). During a mean 4-year follow-up, incident stroke occurred in 52,500 patients (1,338 in cancer survivors, 51,182 in non-cancer). The ERC group showed a lower risk of stroke than the usual care group, regardless of the presence of cancer history(Figure); adjusted hazard ratio [95% confidence interval] 0.67 [0.58-0.76] in cancer survivors, 0.76 [0.74-0.78] in the non-cancer group (p-for-interaction=0.125). The effect of ERC on the risk of ischemic stroke in cancer group was consistent across all subgroups, including different cancer types or use of chemotherapy. Conclusion ERC was associated with a lower risk of ischemic stroke among long-term cancer survivors. An integrated approach incorporating appropriate rhythm control strategies should be considered for cancer survivors with newly diagnosed AF.