With the popular methods of CoMFA and CoMSIA, three-dimensional quantitative structure-activity relationships (QSARs) were newly developed for the toxicity of polybrominated diphenyl ethers (PBDEs). The choice of optimized geometries by density functional theory (DFT) as molecular template and the RMSD-based molecular alignment strategy might mostly contribute to the QSAR improvement, which was highlighted specifically by the increased q2 of 0.870 for CoMFA, 0.887 for CoMSIA, respectively. QSARs analyzes indicated that the steric effects from ortho- and meta-substitution and the correlated hydrophobicities have the greatest impact on the binding affinities of aryl hydrocarbon receptor (AhR) to PBDEs. Though the effects of electrostatics were comparatively inferior in the AhR binding, the aromatic interaction and possible charge transfer proved to be indispensable for toxicity mediation. Consistent with that proposed previously for other structurally similar compounds, such as dioxins and polychlorinated biphenyls, the predictive toxicology was helpful to understand the congener-specificity of toxicity of PBDEs.