A 3D-QSAR study was carried out on 20 cannabinoids for which the binding affinities (K(i)) with respect to CB(1) and CB(2) receptors, determined in the same cell line, were available. For the first time three series of significantly different chemical structures such as Delta(9)-THC analogues, anandamides, and indoles were included in a single 3D-QSAR model, to obtain information on the interactions of all ligands with both CB(1) and CB(2) receptors and on their receptor selectivity. Delta(9)-THC was chosen as the structural template for alignment. The 3D-structure-activity correlation obtained by the GOLPE procedure provided a partial least squares (PLS) model with a very good predictive ability for the CB(1) receptor affinity of all compounds. The model allowed us to identify seven different regions in the space that contribute to explain the above binding affinities. External validation of the interpretation of the 3D-QSAR model was derived from a response-independent procedure such as principal components analysis (PCA). The CB(2) receptor model evidenced, besides the seven regions found for the CB(1) receptor, a new characteristic region for the CB(2) receptor. Another PCA, using 10 GRID probes, provided further evidence of receptor selectivity regions. One region opposite to the amidic NH of CB(1) selective O585 appears to be responsible for the CB(1) selectivity, while an interaction region opposite to the carbonyl of CB(2) selective JWH-015 appears to be involved in the CB(2) binding selectivity.