The inclusion process of four tricyclic antidepressant drugs (carbamazepine, imipramine, dothiepin and doxepin) with β-cyclodextrin (β-CD), as well as their possible interaction types have been investigated theoretically. The data suggest that these drugs are partially encapsulated into the β-CD cavity. The formation of the inclusion complex is predicted to be an enthalpy-driven process in gas phase. Different interactions between these drugs and β-CD should be also possible due to their negative binding energy though their distributions differ greatly. Comparative study of the interactions of these drugs with β-CD has been investigated and their obvious differences in binding energy and enthalpy change suggest that the β-CD can identify the stability of the complex.