In the search of newer and potent antitumor agents, a series of 4β-anilino- 4’-O-demethyl-4-desoxypodophyllotoxin derivatives was subjected to 2D Quantitative Structure Activity Relationship (QSAR) analysis. The statistically significant models were generated and the most robust model for 2D QSAR was obtained using random regression method coupled with stepwise forward backward method using V-Life Molecular Design Suite software version 3.5. The physicochemical descriptors, viz., Most +ve &-vePotential distance, vdWSurface Area, SAMostHydrophilic contributed significantly to the biological activity. About 22 QSAR models were generated, among which three significant models were finally selected on the basis of various statistical parameters such as squared correlation co-efficient (r2), and cross-validated square correlation co-efficient (q2). The statistical values of the three significant models viz. model 1, model 2 and model 3 are as r2 to be 0.9320, 0.9576 and 0.9403 respectively and q2 to be 0.8540, 0.8801 and 0.8137 respectively. The descriptors showed by QSAR study can be used further for studying and designing of new compounds. Consequently, this study may prove to be helpful in the development and optimization of existing antitumor activity of this class of compounds.