A comprehensive, multinational literature search was conducted of all articles published from 1993 to 2003 regarding the cost effectiveness of antidepressant drugs, with special emphasis on comparing third-generation antidepressants (TGAs) with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Information from the collected articles was entered into a database and then analysed to assess the different approaches to cost effectiveness comparisons for the various classes of antidepressants. Factors examined included direct and indirect costs, treatment endpoints, healthcare cost burden and productivity gains for patients successfully treated for depression. Most model-based studies published between 1993 and 2003 supported the cost effectiveness of TGAs compared with TCAs or SSRIs. While the purchase price of TGAs may be greater, cost savings in terms of direct and indirect costs were realised because of the reduced adverse effects of TGAs and subsequent improved patient compliance. Studies based on patient level cost data, however, were less conclusive about the economic benefits of TGAs compared with SSRIs or TCAs. While it may be premature to conclude that TGAs have a significant net economic benefit compared with other antidepressant classes, prescribers and payers may find it helpful when choosing antidepressants for depressed patients to consider that the higher drug prices for TGAs may be offset by savings, in terms of their greater compliance and resultant therapeutic success rates compared with TCAs or SSRIs. Additional research is needed to clarify how cost effectiveness is assessed in different patient populations, such as geriatric patients--who commonly have more co-morbidities and higher total healthcare costs than other patient populations.