Organic selenides, such as Se-alkyl-selenocysteine and derivatives, are active in suppressing chemically induced mammary carcinogenesis in rats. Here the quantitative structure-activity relationship (QSAR) study of ten related alkyl-chalcogens was performed to correlate their structural properties with the measured chemotherapeutic activities (ED50). The CS Gaussian 98 program with Hartree-Fock/3-21G (d) basis set was applied for molecular properties computations of the optimized models. Electron Density on chalcogen (ED(X)) expressed the strongest influence on anticancer activity of the examined molecules. Linear regression model of the alkyl-chalcogens, log(ED50) = f (ED(X)), was obtained with R2=0.964 and cross-validation parameter q2 pre=0.950. Synergy between organo-selenides and vitamin E in chemotherapeutic activity led to propose novel organoselenium-α- tocopheryl esters as potent anticancer agents. Anticancer activities (log(ED50)) of the designed alkyl-seleno/α-tocopheryl esters (S-1 to S-4) were evaluated using the developed QSAR/alkyl-chalcogens model and the most potent chemotherapeutic agents (ED50(S-1): 2.60 ppm and ED50(S-4): 2.55 ppm). On the other side, previously created QSAR model for in vitro anticancer activity (IC50) for α-tocopherol derivatives, log(IC50)=f (NCH3, logDpH 5.0, O-charge) with R2=0.940 and q2 pre=0.879, was employed with IC50 evaluation of the proposed alkyl-seleno/α-tocopheryl esters (S-1 to S-4). Calculated antiproliferative activities of the designed compounds, IC50(S-1): 25.65μM and IC50(S-4): 31.36μM, were significantly stronger than activities of other related anticancer agents, IC50: 4-1461 μM.