A novel approach for the rapid, accurate mass analysis of pharmaceutical solid, liquid, and cream formulations using desorption electrospray ionization (DESI) is described. The method is based on polarity switching and real-time accurate mass measurement in an orthogonal acceleration time-of-flight mass spectrometer fitted with a dual-inlet electrospray ion source. Infusion of a reference compound into one inlet provides a single-point "lock mass" for accurate mass measurement. The other inlet sprays solvent at the sample being investigated using DESI. Minimal sample preparation was required. Results demonstrate the ability to acquire simultaneously positive and negative accurate mass DESI data within the same acquisition, thus negating the need for repeat analysis in each ion mode. In this paper, drugs that preferentially ionize in a particular mode depending on their physiochemical properties are presented. Mass accuracy to within 2 mTh was obtained for all drugs sampled.