Comparative molecule/pseudo receptor interaction analysis (CoMPIA) is developed as a novel 3D-QSAR method by adding postulated pseudo receptor and GA-optimized probe into comparative molecular field analysis (CoMFA). CoMPIA is used to find the pseudo receptor mode by optimizing probe distributions and to establish the optimal model of high qualities and good interpretations. Correlative coefficient R2, cross-validated correlative coefficient Q2 and root mean square error RMSEP of the resulting model are 0.940, 0.868 and 0.502, respectively by applying CoMPIA to quantitative structure-activity relationship (QSAR) of 31 classical steroids.