Recent work implicating the cannabinoid receptors in a wide range of human pathologies has intensified the need for reliable QSAR models for drug discovery and lead optimization. Predicting the ligand selectivity of the cannabinoid CB 1 and CB 2 receptors in the absence of generally accepted models for their structures requires a ligand-based approach, which makes such studies ideally suited for quantum-chemical treatments. We present a QSAR model for ligand–receptor interactions based on quantum-chemical descriptors (an eQSAR) obtained from PM3 semi-empirical calculations for a series of phenyl-substituted cannabinoids based on a ligand with known in vivo activity against glioma [Duntsch, C.; Divi, M. K.; Jones, T.; Zhou, Q.; Krishnamurthy, M.; Boehm, P.; Wood, G.; Sills, A.; Moore. B. M., II. J. Neuro-Oncol., 2006, 77, 143] and a set of structurally similar adamantyl-substituted cannabinoids. A good model for CB 2 inhibition ( R 2 = 0.78 ) has been developed requiring only four explanatory variables derived from semi-empirical results. The role of the ligand dipole moment is discussed and we propose that the CB 2 binding pocket likely possesses a significant electric field. Describing the affinities with respect to the CB 1 receptor was not possible with the current set of ligands and descriptors, although the attempt highlighted some important points regarding the development of QSAR models.