One of the main steps in choosing the drug nanoparticle production processes by supercritical carbon dioxide (SC-CO2) is determining the solubility of the solid solute. For this purpose, the solubility of Ketoconazole (KTZ) in the SC-CO2, binary system, as well as in the SC-CO2-menthol (cosolvent), ternary system, was measured at 308–338 K and 12–30 MPa using the static analysis method. The KTZ solubility in the SC-CO2 ranged between 0.20 × 10–6 and 8.02 × 10–5, while drug solubility in the SC-CO2 with cosolvent varied from 1.2 × 10–5 to 1.96 × 10–4. This difference indicated the significant effect of menthol cosolvent on KTZ solubility in the SC-CO2. Moreover, KTZ solubilities in the two systems were correlated by several empirical and semiempirical models. Among them, Sodeifian et al., Bian et al., MST, and Bartle et al. models can more accurately correlate experimental data for the binary system than other used models. Also, the Sodeifian and Sajadian model well fitted the solubility data of the ternary system with AARD% = 6.45, Radj = 0.995.