The membrane-coated fiber (MCF) array technique was previously demonstrated to be a rapid, quantitative assessment of the percutaneous absorption of volatile compounds, capable of studying chemical mixtures and their synergistic effects. In particular, three commercially available fiber coatings (polydimethylsiloxane, polyacrylate and carbowax) were shown to be representative of molecular interactions relevant to skin absorption. This study evaluated the potential use of these fibers as a high throughput screening approach for topical formulations. More specifically, the MCFs were evaluated for their ability to predict the skin permeability of caffeine (CF), cortisone (CT), mannitol (MN) and salicylic acid (SA) applied in water or ethanol as unsaturated and/or saturated concentrations, using an additional extraction step to obtain analytes appropriate for liquid chromatography. Compound extraction from a donor solution was carried out by fiber immersion for a set period of time. The compound was then re-extracted into acetonitrile and quantitated by liquid chromatography coupled to a mass spectrometer. Radiolabel equivalents of the compounds were analyzed in a similar manner with the exception of detection method used. Fiber extraction of radiolabeled compounds (CF, MN, SA in water) was proved to be unsuccessful, whereas the extraction of their non-radiolabeled equivalents (CF, CT, SA) revealed poor linearity, and poor between-day and within-day reproducibility. Similar unsatisfactory results were observed regardless of whether a single fiber was used, or whether multiple fibers were used simultaneously. Furthermore, incompatibility between the MCF and solvent (vehicle) was observed, which disputes its potential use as a formulation screening technique. On the basis of these findings, the MCF array is not suitable to describe the vehicle effects on skin absorption of non-volatile compounds.