Estrogen mediates its action following binding to the estrogen receptor to form an estrogen-receptor complex. The complex initiates gene transcription and produces estrogen-induced cell and/or tissue responses, i.e., estrogenic actions. High doses of estrogen can be used effectively as a contraceptive but are associated with side effects. Considering the long-term benefit-to-risk ratio of estrogen analogs as oral contraceptives, the present study was performed to deduce the active pharmacophore features required to differentiate the anti-fertility potency from the estrogenic activity of the steroidal motif. Implementing classical quantitative structure-activity relationship (QSAR) studies, substitution by an electron-donating group at the C17 position and the presence of a hydrogen bond acceptor at C11, along with the orientation and conformational rigidity of the molecule, were found to be critically important features for estrogenic potency, including anti-fertility activity. However, low electron density at C2 and high electronegativity at C16, which may be due to substitution on those and/or neighboring atoms, favor contraceptive potency, whereas high electron density at C5 and substitution by an electron-withdrawing group at C7, which may confer hydrophobicity on the steroidal scaffold and an overall increment of electron affinity of the molecule, are favorable for estrogenicity. Further CATALYST-based 3D space modeling demonstrates that the presence of the aromatic ring (ring A), hydrophobic zone (ring B), and hydrogen bond acceptor at C17 in ring D, along with steric influence due to conformational rigidity of the compound, impart estrogenic contraceptive activity, but the presence of a second acceptor in ring A, and the critical distances between these features, selectively differentiate the anti-fertility potency from the estrogenic activity. © Springer-Verlag 2008.