A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have beensynthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2' ligands.Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl groupshowed low nM inhibitory activities against wild-type HIV-1 protease. Selected compounds were furtherevaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for theirantiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containingphenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. Acomparison of the inhibitor-protease structures with the LPV-protease structure provides valuable insightinto the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures andknowledge of structure-activity relationships, new inhibitors can be designed with enhanced enzymeinhibitory and antiviral potencies.