Combinatorial methods have emerged as valuable tools for the discovery of proteins; nucleic acids, and small molecules with novel structures and properties. While combinatorial methods can generate de novo proteins with native-like properties, finding such proteins in libraries containing an abundance of non-native structures has proved difficult and tedious. To overcome these-difficulties, we developed a rapid screen for native-like properties. The screen uses electrospray mass spectrometry (ESMS) to monitor the hydrogen-deuterium (H-D) exchange kinetics in semicrude samples of de novo proteins expressed in Escherichia coli. To demonstrate the utility of the approach, we screened two libraries of de novo sequences and identified proteins whose amide protons were protected from exchange with solvent. The results of the screen correlate well with orthogonal methods for detecting native-like structures. As protection of amide protons from exchange is a hallmark of well-folded proteins, this screen can be used to identify native-like proteins from combinatorial Libraries containing both native-like and molten globule-like structures. Moreover, since the screen can be applied to semicrude samples and does not require extensive protein purification, it can be used for medium throughput screening of large combinatorial libraries.