QSAR analysis has been used to identify the essential structural requirements for increasing the inhibitory activities of selected bufadienolides from the Chinese drug Ch'an Su (and other sources) against the primary liver carcinoma cell line PLC/PRF/5 (PLC) and the derived colchicine-resistant line (COL). The variable substituent domain of the proposed pharmacophore of the bufadienolides was investigated using a Comparative Molecular Field Analysis (CoMFA) approach. A model with considerable predictive ability was obtained. In addition, the CoMFA results agreed well with the pharmacophore bufadienolide model for the parent PLC line proposed earlier.