In comparison to primary readout ranking, our approach outperforms it on 15 datasets, with average improvements of 50%, 13% and 14% in terms of relative precision, enrichment factor and BEDROC. This is especially impressive considering that ranking compounds according to their primary HTS readout is the industry standard for hit triaging in HTS campaigns. The relatively low performance of this method could be due to the fact that assay interferents can be outliers in terms of primary readout, for example by exhibiting very strong auto-fluorescence, causing them to be at the top of the primary readout ranking. As such, this benchmark shows that our data-driven approach is more efficient at finding true actives than the currently used criteria for HTS hit triaging.