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Warfarin is the most recommended anticoagulant drug for patients undergoing heart valve replacement. However, due to the narrow therapeutic window and individual dose, the use of warfarin needs more advanced technology. We used the data collected from a multi-central registered clinical system all over China about the patients who have undergone heart valve replacement, subsequently divided into three groups (training group: 10673 cases; internal validation group: 3558 cases; external validation group: 1463 cases) in order to construct a hybrid model with genetic algorithm and Back-Propagation neural network (BP-GA), For testing the model’s prediction accuracy, we used Mean absolute error (MAE), Root mean squared error (RMSE) and the ideal predicted percentage of total and dose subgroups. In results, whether in internal or in external validation group, the total ideal predicted percentage was over 58% while the intermediate dose subgroup manifested the best. Moreover, it showed higher prediction accuracy, lower MAE value and lower RMSE value in the external validation group than that in the internal validation group (p < 0.05). In conclusion, BP-GA model is promising to predict warfarin maintenance dose.