The affinity of the classical β2 adrenoceptor-selective inverse agonist ICI118,551 is notoriously lower for porcine β2 adrenoceptors (p2βAR) than for human β2 adrenoceptors (hβ2AR) but molecular mechanisms for this difference are still unclear. Homology 3-D models of pβ2AR can be useful in predicting similarities and differences, which might in turn increase the comparative understanding of ligand interactions with the hβ2AR. In this work, the pβ2AR amino acid sequence was used to carry out homology modeling. The selected pβ2AR 3-D structure was structurally and energetically optimized and used as a model for further theoretical study. The homology model of pβ2AR has a 3-D structure very similar to the crystal structures of recently studied hβ2AR. This was also corroborated by sequence identity, RMSD, Ramachandran map, TM-score and docking results. Upon performing molecular docking simulations with the AutoDock4.0.1 program on pβ2AR, it was found that a set of well-known β2AR ligands reach two distinct binding sites on pβ2AR. Whereas one of these sites is similar to that reported on the hβ2AR crystal structure, the other can explain some important experimental observations. Additionally, the theoretical affinity estimated for ICI118,551 closely agrees with affinities estimated from experimental in vitro data. The experimental differences between the human/porcine β2ARs in relation to ligand affinity can in part be elucidated by observations in this molecular modeling study.