In this study, ultrafine clobetasol propionate (CP) particles were produced by rapid expansion of supercritical solution (RESS). Particle size and morphology of CP were examined using eleven experiments based on 2 level full factorial design and the effects of extraction pressure (200-260 bar), pre-expansion temperature (70-110 degrees C) and menthol (co-solvent) weight fraction (3-7 wt.%) were evaluated. The size was measured by Nanosizer(R) and processed particles were analyzed using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared analysis (FT-IR) and differential scanning calorimetry (DSC). The mean particle size of processed CP was between 95 nm and 318.8 nm. According to the statistical analysis, pressure had the most significant effect on the particles size with the lowest probability value (0.001) and highest Fischer value (53.1). (C) 2015 Elsevier B.V. All rights reserved.