With the help of X-ray structural analyses of drug-resistant HIV proteases and molecular modeling, a new type of inhibitor with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild type and drug-resistant mutants and further supports that FIV protease is a useful model for drug-resistant HIV proteases, which often are developed through reduction in size of the binding region for the P3 group or the combined P3 and P1 groups.