A novel method of detecting proteins at low concentration based upon electrospray ionization–mass spectrometry and gas-phase proton transfer reactions is described. In this technique the signal that is spread over a broad mass range due to the distribution of multiply charged ions generated in electrospray is focused into a singly-charged, low mass ion. The experiments performed on a quadrupole ion trap involve accumulating the ions of the biopolymer, allowing these ions to react with a strong neutral base, and recording the intensity of the singly-charged product in a final mass analysis scan. Concentration detection limits for high-mass proteins may be improved by over two orders of magnitude using this approach. Targeted compounds can be detected at low nanomolar levels using moderate reaction times with a strong base. © 1997 John Wiley & Sons, Inc. J Micro Sep9: 523–528, 1997