A method of rapid expansion of supercritical solutions with solid cosolvent (RESS-SC) was applied, for the first time, to precipitate nanoparticles of Letrozole (LTZ). Solubility of LTZ, as a poorly water-soluble drug, was measured under various conditions in supercritical CO2 with/without menthol as cosolvent. The solubility of LTZ in ternary system (with solid cosolvent) was increased 7.1 times as large as that of binary system (without solid cosolvent). Then, influences of temperature, pressure, solid cosolvent and spray distance on the size and morphology of the particles were investigated by Taguchi technique. The analysis of variance results showed that, temperature and pressure had the most and least significant impacts on the size-reduction of nanoparticles, respectively. The particles were characterized using SEM, DLS, XRD, FTIR and DSC. Experimental observations revealed that the LTZ particles were nanosized from the original average size of 30 mu m to the smallest average size of 19 nm.