The present quantitative structure-activity relationship (QSAR) study attempts to explore the structural and physicochemical requirements of mannitol derivatives for HIV protease inhibitory activity using linear free energy related model of Hansch. QSAR models have been developed using electronic (Hammett sigma), hydrophobicity (pi), and steric (molar refractivity and STERIMOL L, B1, and B5) parameters of phenyl ring substituents of the compounds along with appropriate dummy variables. Whole molecular descriptors like partition coefficient (logP(calcd)) and molar refractivity (MR) were also tried as additional descriptors. Statistical techniques like stepwise regression, multiple linear regression with factor analysis as the data preprocessing step (FA-MLR), principal component regression analysis (PCRA), and partial least squares (PLS) analysis were applied to identify the structural and physicochemical requirements for HIV protease inhibitory activity. The generated equations were statistically validated using leave-one-out technique. The quality of equations obtained from stepwise, FA-MLR, PCRA, and PLS are of acceptable statistical range (explained variance ranging from 74.0% to 80.5%, while predicted variance ranges from 70.3% to 77.1%). The coefficient of molar refractivity shows that the activity decreases with increase in volume. Lipophilicity of the para substituents at Y position is conducive to the activity while lipophilicity of the para substituents at X position is detrimental to the activity. The coefficients of molar refractivity (mr(Y_p)) and STERIMOL parameters for para substituents at X and Y positions (B1(X_p) and B5(Y_p)) of the phenyl rings indicate that the width of the substituents at X position and the overall size of para substituents at Y position are the detrimental factors for the activity. The fluoro substituent at ortho position (Y) decreases the activity when compared to the corresponding unsubstituted congener. Presence of hydrogen bond donor groups at para position (Y) also reduces the activity. Additionally, presence of substituent at ortho position (X) and the presence of substituent at para position (Y) are conducive for the activity. Presence of fluorine at X and Y positions also increases the activity.