In this study, the retention behaviors of pharmaceutical and drug-like compounds in supercritical fluid chromatography (SFC) with polar stationary phases were evaluated using linear solvation energy relationships (LSERs). We used more than 200 compounds, including mono-, di-substituted benzenes, and other marketed drugs with a wide range of solvation descriptors. The dominant contribution to positive retention was the hydrogen bond donor acidity of the solutes, particularly for pyridine and amino columns. That factor is determined by the difference in basicity between the mobile and stationary phases. Another significant contributor to retention behavior was the hydrogen bond acceptor basicity of the solutes made particularly for diol and amino columns. The hydrogen bond donating ability is small for cyano and pyridine stationary phases (or should be zero) since those two phases lack hydrogen bond donor groups. The LSER results showed that the SFC retention behavior of compounds using carbon dioxide-methanol with polar stationary phases was close to that reported for normal phase LC using hexane-methanol. As expected, mobile phases containing high percentages of modifier resulted in decreased retention times for most compounds. A greater knowledge of the nature of solute/stationary phase and solute/mobile phase allows a more rapid and efficient choice in high-throughput screening of compound libraries.