The knowledge of solubility of solid solute in supercritical carbon dioxide is crucial for the design and optimization of relevant processes in food and pharmaceutical industries. We systematically examine the accuracy of a first-principles thermodynamic model PR + COSMOSAC EOS in predicting solid solute solubility in supercritical carbon dioxide and compare to that of a group contribution model PSRK EOS. Molecular structure, heat of fusion, and melting temperature of the investigated compound are the only required information for the solubility calculation. All other information can be obtained from quantum mechanical solvation calculations. The average logarithmic deviation in mole fraction (ALD-y) in predicting 99 solid solute solubility in supercritical carbon dioxide (a total of 2450 data points with a temperature range of 298 K–473 K and a pressure range of 45 bar–500 bar) was found to be 0.79 (or about 510%). This indicates that the PR + COSMOSAC EOS is able to reasonably estimate solubility order of magnitude without any adjustable model parameter and provide useful solubility information, especially when no experimental solubility data is available.