Background: Prophylactic anticoagulation was recommended for stroke prevention in patients with hypertrophic cardiomyopathy(HCM) and atrial fibrillation(AF) regardless of CHA2DS2-VASC score but the strategy was in a dilemma for patients with contraindication to antigulants. Aims: To estimate the safety and efficacy of left atrial appendage occlusion(LAAO) in HCM patients with atrial fibrillation(AF). Methods and results: This prospective study included 25 HCM patients(age 70.04±11.62years, 72% male, 16/25(64.00%) had prior stroke) with AF eligible for LAAO. Clinical outcomes and echocardiographic parameters were collected and assessed during procedure and follow-up(3, 6, and 12months post-procedure). The composite safety outcomes included all-cause death, major bleeding and procedure-related complications. The primary efficacy outcome was defined as ischemic stroke and systemic embolization. Successful implantation was achieved in 24 patients(96%) using Watchman device without severe peri-device leaks (PDL), while one patient developed new-onset thrombus before access puncture on the operative day. Median follow-up was 1.5 years with a total of 38.1 patient-years. Only one patient experienced non-disabling ischemic stroke. The occurrence of major bleeding was 1/24(4.17%), with a remarkable reduction in annual 3 bleeding risk by 56.18% compared to the predicted rate. Device-related thrombus(DRT) was detected in 3/24(12.50%) patients. Neither serious procedure-related complications nor death events were reported in our study. Conclusion: Our study suggested the feasibility and safety of LAAO in HCM patients for stroke prevention. Whereas, thrombus formation remains a concern depending on hemodynamic abnormality associated with HCM. Further follow-up visits on larger sample size would facilitate the evaluation of LAAO in this high-risk cohort.