Achiral pyran-2-one analogs possessing a 3-S-(2-alkylphenyl) group were determined to be high-affinity inhibitors for human immunodeficiency virus (HIV) protease (PR). Crystallographic, modeling, and structure-activity studies led to the 3-S-(2-tert-butylphenyl) moiety as an apparent optimal group to access the S-2’/S-1’ pockets of the enzyme. Further optimization led to an inhibitor, 3-[(2-tert-butylphenyl)sulfanyl]-4-hydroxy-6-(3-methylphenyl)- pyran-2-one (14), possessing a K-i of 3 nM. An X-ray crystallographic structure of an inhibitor, 4-hydroxy-3-[(2-isopropylphenyl) sulfanyl]-6-phenylpyran-2-one (8), bound to HIV PR showed that the 3-S-(2-isopropylphenyl) group occupied the P-2’ and P-1’ pockets, while other crucial interactions were common to those found with other pyran-2-one analogs. The high potency observed for this series may be due, in part, to the restrictions on the intramolecular collapsibility of these molecules in aqueous solution, leading to a highly favorable hydrophobic effect on binding. Herein we report a novel P-2’/P-1’ achiral ligand which results in a tight-binding inhibitor that occupies only three pockets in the enzyme and exhibits a unique pattern of in vitro resistance.