The pregnane X receptor (PXR) regulates the expression of genes involved in xenobiotic metabolism and transport. In vitro methods to screen for PXR agonists are used widely. In the current study, computational models for human PXR activators and PXR nonactivators were developed using recursive partitioning (RP), random forest (RF), and support vector machine (SVM) algorithms with VolSurf descriptors. Following 10-fold randomization, the models correctly predicted 82.6-98.9% of activators and 62.0-88.6% of nonactivators. The models were validated using separate test sets. The overall ( n = 15) test set prediction accuracy for PXR activators with RP, RF, and SVM PXR models is 80-93.3%, representing an improvement over models previously reported. All models were tested with a second test set ( n = 145), and the prediction accuracy ranged from 63 to 67% overall. These test set molecules were found to cover the same area in a principal component analysis plot as the training set, suggesting that the predictions were within the applicability domain. The FlexX docking method combined with logistic regression performed poorly in classifying this PXR test set as compared with RP, RF, and SVM but may be useful for qualitative interpretion of interactions within the LBD. From this analysis, VolSurf descriptors and machine learning methods had good classification accuracy and made reliable predictions within the model applicability domain. These methods could be used for high throughput virtual screening to assess for PXR activation, prior to in vitro testing to predict potential drug-drug interactions.