Background: Left atrial appendage occlusion (LAAO) is a potential alternative to oral anticoagulants in selected patients with atrial fibrillation (AF). Compared with anticoagulants, LAAO decreases major bleeding risk, but there is uncertainty regarding the risk for ischemic stroke compared with anticoagulation. Objective: To determine the optimal strategy for stroke prevention conditional on a patient's individual risks for ischemic stroke and bleeding. Design: Decision analysis with a Markov model. Data Sources: Evidence from the published literature informed model inputs. Target Population: Women and men with nonvalvular AF and without prior stroke. Time Horizon: Lifetime. Perspective: Clinical. Intervention: LAAO versus warfarin or direct oral anticoagulants (DOACs). Outcome Measures: The primary end point was clinical benefit measured in quality-adjusted life-years. Results of Base-Case Analysis: The baseline risks for stroke and bleeding determined whether LAAO was preferred over anticoagulants in patients with AF. The combined risks favored LAAO for higher bleeding risk, but that benefit became less certain at higher stroke risks. For example, at a HAS-BLED score of 5, LAAO was favored in more than 80% of model simulations for CHA2DS2-VASc scores between 2 and 5. The probability of LAAO benefit in QALYs (>80%) at lower bleeding risks (HAS-BLED score of 0 to 1) was limited to patients with lower stroke risks (CHA2DS2-VASc score of 2). Because DOACs carry lower bleeding risks than warfarin, the net benefit of LAAO is less certain than that of DOACs. Results of Sensitivity Analysis: Results were consistent using the ORBIT bleeding score instead of the HAS-BLED score, as well as alternative sources for LAAO clinical effectiveness data. Limitation: Clinical effectiveness data were drawn primarily from studies on the Watchman device. Conclusion: Although LAAO could be an alternative to anticoagulants for stroke prevention in patients with AF and high bleeding risk, the overall benefit from LAAO depends on the combination of stroke and bleeding risks in individual patients. These results suggest the need for a sufficiently low stroke risk for LAAO to be beneficial. The authors believe that these results could improve shared decision making when selecting patients for LAAO.