Because of its limited water solubility, the anti-HIV drug atazanavir requires a unique drug delivery mechanism to improve its therapeutic efficacy and safety. The primary purpose of this study was to develop a method for producing liquisolid powder compacts (LSPCs), which have been shown to be a promising solubility enhancement technique for effective oral administration of BCS class II drugs. Therefore, a unique LSPC formulation of the BCS class II drug atazanavir was developed in an effort to enhance its oral administration. Transcutol HP, propylene glycol, span 20, and span 80 were used in the solubility tests. Transcutol HP was used in the formulation of the LSPCs since it is a non-volatile solvent. In order to measure how various formulation factors affect LSPC performance, a 32 -factorial design was used. Dependent variables were disintegration time and cumulative drug release percentage; independent variables were the percent of ataznavir in transcutol HP (X1) and the percent of sodium starch glycolate (X2). High dissolving profile with acceptable tablet characteristics were achieved in LSPCs of Atazanavir prepared with propylene glycol at the optimal drug concentration. No drug-polymer interactions were found using Fourier transform infrared spectroscopy (FTIR), and Atazanavir was converted from a crystalline to an amorphous state using differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The potential of LSPCs for increased permeation of Atazanavir over the rat intestinal barrier was also highlighted by permeation tests performed in isolated rat intestine. The better oral administration of Atazanavir shown by the increased penetration of clonazepam from LSPCs formulation through rat gut warrants further investigation.