A high throughput screening (HTS) technique was developed for the rapid evaluation of displacers for the purification of antisense oligonucleotides using anion-exchange systems. By employing this technique, a large number of potential displacers with a variety of structural properties were evaluated in parallel, dramatically decreasing the time required for displacer discovery. A database was generated containing molecular descriptors of the screened displacer probes as well as their displacement data obtained from the HTS experiments. A subset of the probe data was used to derive a predictive quantitative structure efficacy relationship (QSER) model using a partial least squares (PLS) approach. The resulting model was well correlated with r(2) = 0.915. In addition, the model was shown to predict the molecules not included in the model successfully. The results presented in this paper demonstrate the utility of the HTS technique for the rapid evaluation of displacers for the purification of antisense oligonueleotides. These results applied in concert with the QSER modeling, can aid in the a priori design of high-affinity displacers for anion-exchange systems.