A study of the quantitative structure activity relationships (QSARs) was performed based on the binding affinity (pKi) values of 32 protein kinase C (PK-C) ligands. The QSAR study was carried out by using both three-dimensional descriptors (the steric and electrostatic CoMFA fields) and the physicochemical properties (logP values). The CoMFA analysis provided a reasonable QSAR model, with a cross-validated q2 value of 0.671 and a conventional r2 value of 0.956, which was confirmed by the satisfactory prediction of the experimental binding affinity (pKi) values for a series of 3-alkylidene-5,5-disubstituted tetrahydro-2-furanones included in the test set. The resultant QSAR model will be useful for designing highly potent and selective PK-C ligands.