Estrogens are involved in the development and homeostasis of several female tissues. Their physiological effects are mediated by the estrogen receptor (ER), a ligand-inducible nuclear transcription factor. The flexibility of the ER ligand-binding cavity allows the binding of a series of structurally diverse compounds. Their potential use as contraceptives, breast cancer chemotherapy and osteoporosis treatment have been investigated. Tamoxifen and fulvestrant are clinically important compounds that are capable of inhibiting the growth of breast cancer cells, however, they present some undesirable adverse effects. Thus, drug research advances toward the development of more potent and selective modulators that ideally will not present the same adverse effects. This present work describes the generation of a 3D QSAR CoMFA model employing a data set of 128 flavanoids, benzoxathiins and benzodithiins as ER modulators. The IC₅₀ values vary from 1.1 μM to 0.3 nM and were measured under the same experimental conditions. The 3D structures of the modulators were optimized and positioned in binding cavity of the ER crystallographic structure (PDB code 1XP1) using the docking program GOLD 2.1. Steric and electrostatic fields were defined for the aligned data set using a sp³ carbon atom probe carrying a +1 net charge. The models were developed using the CoMFA module implemented in Sybyl 7.1. The IC₅₀ values were converted to the corresponding pIC₅₀ and used as dependent variables in the QSAR investigations. Region focusing was used to increase model resolution. Significant statistical coefficients (q² of 0.81 and r² of 0.93 with 7 optimum components) were obtained, indicating the potential of the model for untested compounds. The models were then used to predict the potency of 28 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results. The final QSAR model and the information obtained from 3D contour maps should be useful for the design of novel estrogen modulators having improved potency.