For initial hit identification in fragment-based drug design, NMR is one of the preferred methods, with the well-established ligand screening experiments T1ρ, waterLOGSY and STD. Here, we present a new, perfect echo-based experiment with superior binding sensitivity, the PEARLScreen. The sensitivity enhancement is based on longer relaxation delays as well as active exchange broadening, enabled by the perfect echo scheme. This allowed a reduction of the protein concentration by up to one order of magnitude in comparison to the conventional experiments on the same screening setup without losing binding sensitivity. The experiment was tested throughout the whole field range of commercially available spectrometers from 80 to 1200 MHz, where at the highest field even a reduction of the required protein amount by a factor of 40 is within reach, thanks to larger compound mixtures and enhanced exchange effects. Based on the superior performance already on standard NMR setups, we expect the PEARLScreen to become the standard screening experiment for 1H-detected ligand screening.