From 2006 to 2009, the number of new cases of human immunodeficiency virus type 1 (HIV-1) in the United States increased. Many have questioned whether this is due to medication response, therapy, viral mutation, infection rates, or a lack of improved knowledge on virus protection. Regardless of the causes, new methods of prevention, such as education against contracting the virus, and therapy to make persons afflicted with the virus suffer from a manageable chronic condition are required. Because protease is required for the life cycle of HIV virions, protease inhibitors have been the most widely used anti-HIV drugs. However, because of the virus's ability to evolve at such an alarming rate, many researchers and physicians remain unconvinced and skeptical that antiretroviral medications will stay effective against it. Therefore, we developed topomer CoMFA (Comparative Molecular Field Analysis) and HQSAR (Hologram Quantitative Structure Activity Relationship) models on a series of N-aryl-oxazolidinone-5-carboxamides which is HIV-1 protease inhibitors. The developed models show good statistics in terms of q2 and r2 values. The best predictions obtained with topomer CoMFA model (r2 = 0.967, q2 = 0.874) and HQSAR model (r2 = 0.973, q2 = 0.902). The HQSAR model was fitted to predict the biological activity using atom, bond, connections and chirality as parameters and fragment size (6-9). The validity of developed models was confirmed by test set and good predictive correlation coefficient for topomer CoMFA (0.9576) and HQSAR (0.913) is found. The contour plot of topomer CoMFA suggests that at phenylsulfonamide moiety (R1 fragment) sterically bulky and electropositive groups are favored by the model for enhancing the activity. In addition, the atomic contribution map of HQSAR suggests that 4-methoxy, dioxolane and amino groups at phenylsulfonamide moiety are preferred and, moreover, 3 and 4 acetyl groups at phenyloxazolidinone moiety are favored.