Competitive host-guest chemistry on a desorption electrospray ionization mass spectrometry (DESI MS) platform is presented here as the basis for a rapid and quantitative screening method for assessing the quality of Tamiflu capsules with minimal sample preparation. Oseltamivir, the active ingredient in Tamiflu, is an orally active neuraminidase inhibitor antiviral. The high cost and demand for this drug has made it a target for counterfeiters, and reports of counterfeit Tamiflu capsules have already appeared. This urges the development of rapid and sensitive tools for Tamiflu authentication. The method presented here is based on the selective recognition of oseltamivir by crown ethers added to the DESI spray solvent. Crown ethers with various ring sizes were evaluated, all being observed to form stable host-guest complexes with protonated oseltamivir. The relative gas phase stability of each of the host-guest complexes was assessed and the results compared with dispersion-corrected density functional theory. Competive experiments with various pairs of crown ethers were used to assess the relative binding selectivities for oseltamivir. The abundance ratio of the formed complexes was observed to be dependent on the amount of analyte present on the surface of the sample, and independent of DESI geometric factors. These competitive reactions were then successfully tested as a means for the rapid quantitation of oseltamivir by reactive DESI MS without the need for an internal standard.