Objectives: The purpose of this study was to provide data on the long-term efficacy and safety of left atrial appendage occlusion (LAAO) in patients with atrial fibrillation (AF) and chronic thrombocytopenia (cTCP).Methods: Between January 2016 and December 2018, a total of 32 AF patients with thrombocytopenia (platelet count <100*10∧9/L) undergoing LAAO at our center were identified and their outcomes were compared with a propensity-matched cohort (match ratio 1:5) of patients without cTCP who had also been indicated for LAAO.Results: Between the cTCP patients and the control group, no difference was found on the incidence of stroke (0 vs. 3.13%, p = 0.592), systematic thromboembolisation (0 vs. 0.63%, p > 0.9) and device-related thrombus (DRT) (3.13 vs. 2.50%, p > 0.9). Major (12.50 vs. 3.75%, p = 0.065) and minor bleeding (15.63 vs. 1.25%, p = 0.002) was more frequent in cTCP patients but no statistical difference was reached in major bleeding. Moreover, thrombocytopenia was also identified as an independent predictor of any bleeding events (OR: 8.150, 95% CI: 2.579–25.757, p < 0.001), while an inverse relationship between higher absolute platelet count and stroke events was revealed (OR: 1.015; 95% CI: 1.002~1.029, p = 0.022). However, in both groups we saw a significant reduction in observed annualized rates of non-procedural complications compared with the predicted values. In the cTCP and control groups, clinical thromboembolism was reduced by 100 and 74.32%, and major bleeding by 42.47 and 71.67%, respectively.Conclusion: Our preliminary results indicate that LAAO using the Watchman device could be a safe and effective means of preventing stroke in AF patients with or without thrombocytopenia, but bleeding complications should be monitored intensively in cTCP patients.