Three methods, named as synchronous, side-by-side, and tandem development methods, of separating any two or more physicochemical effects in 3D quantitative structure-activity relationships (QSAR) have been investigated with GRID force field using a comparative molecular field analysis (CoMFA) approach. In general, the correlations obtained from all three methods are in excellent agreement with the correlations of the traditional QSAR. The advantages and disadvantages of each method are discussed. The results reinforce the application of the CoMFA methodology in 3D-QSAR studies describing the electronic, steric, and hydrophobic effects using the H⁺, CH₃, and H₂0 probes.