Three-dimensional (3D) quantitative structure-activity relationship (QSAR) studies of 44 curcumin-related compounds have been carried out based on our previously reported result for their anticancer activity against pancreas cancer Panc-I cells and colon cancer HT-29 cells. The established 3D-QSAR models from the comparative molecular field analysis (CoMFA) in training set showed not only significant statistical quality, but also satisfying predictive ability, with high correlation coefficient values (R12= 0.911, R22= 0.985) and cross-validation coefficient values (q2= 0.580, q22= 0.722). Based on the CoMFA contour maps, some key structural factors responsible for anticancer activity of these series of compounds were revealed. The results provide some useful theoretical references for understanding the mechanism of action, designing new curcumin-related compounds with anticancer activity and predicting their activities prior to synthesis.