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Accurate identification of protein–DNA binding sites is significant for both understanding protein function and drug design. Machine-learning-based methods have been extensively used for the prediction of protein–DNA binding sites. However, the data imbalance problem, in which the number of nonbinding residues (negative-class samples) is far larger than that of binding residues (positive-class samples), seriously restricts the performance improvements of machine-learning-based predictors. In this work, we designed a two-stage imbalanced learning algorithm, called ensembled hyperplane-distance-based support vector machines (E-HDSVM), to improve the prediction performance of protein–DNA binding sites. The first stage of E-HDSVM designs a new iterative sampling algorithm, called hyperplane-distance-based under-sampling (HD-US), to extract multiple subsets from the original imbalanced data set …