Rigorously validated quantitative structure-activity relationship (QSAR) models have been developed for 48 antagonists of the dopamine D1 receptor and applied to mining chemical datasets to discover novel potential antagonists. Several QSAR methods have been employed, including comparative molecular field analysis (CoMFA), simulated annealing-partial least squares (SA-PLS), k-nearest neighbor (kNN), and support vector machines (SVM). With the exception of CoMFA, these approaches employed 2D topological descriptors generated with the MolConnZ software package (EduSoft, LLC. MolconnZ, version 4.05; http://www.eslc.vabiotech.com/ [4.05], 2003). The original dataset was split into training and test sets to allow for external validation of each training set model. The resulting models were characterized by cross-validated R2 (q2) for the training set and predictive R2 values for the test set of (q2/R2) 0.51/0.47 for CoMFA, 0.7/0.76 for kNN, R2 for the training and test sets of 0.74/0.71 for SVM, and training set fitness and test set R2 values of 0.68/0.63 for SA-PLS. Validated QSAR models with R2 > 0.7, (i.e., kNN and SVM) were used to mine three publicly available chemical databases: the National Cancer Institute (NCI) database of ca. 250,000 compounds, the Maybridge Database of ca. 56,000 compounds, and the ChemDiv Database of ca. 450,000 compounds. These searches resulted in only 54 consensus hits (i.e., predicted active by all models); five of them were previously characterized as dopamine D1 ligands, but were not present in the original dataset. A small fraction of the purported D1 ligands did not contain a catechol ring found in all known dopamine full agonist ligands, suggesting that they may be novel structural antagonist leads. This study illustrates that the combined application of predictive QSAR modeling and database mining may provide an important avenue for rational computer-aided drug discovery.