With the help of PM3 calculations using cache software QSAR study of two set of derivatives of HIV inhibitors have been made. These belong to protease inhibitors group. The parent compounds of protease inhibitors are urea isostere and other isostere derivatives. The correlation coefficient values of QSAR models are above 0.70. The combination of descriptors providing the best correlation coefficient value are heat of formation(ïHf), total energy(TE), highest occupied molecular orbital (ï¥HOMO) and electronegativity (ï£). The best combinations have been used to predict the activity of fourteen new derivatives of urea isostere. The predicted activities of new derivatives have correlation coefficient above 0.80.