OBJECTIVES: German HTA-Agency (IQWIG) has published its preliminary report plan for Order G09-01 "Cost-benefit analysis of venlafaxine, duloxetine, bupropion and mirtazapine in comparison to other prescription drug treatments" (version 1.0, updated 05-09-2011). This report plan provides important indicators, on how and to what extent innovative drugs are to be reimbursed by German statutory health insurances (SHI). METHODS: IQWIG conducts a cost-benefit analysis that can be divided into five steps with main focus on Mixed Treatment Comparison (MTC). The individual steps in the cost-benefit analysis are largely dependent upon one another, since the results of one step serve as the foundation for the next step of the analysis. It is critical to note that IQWIG compares the four individual antidepressants to active agent categories such as serotonin reuptake inhibitors (SSRIs), without having previously conducted a benefit analysis for these active agent groups. RESULTS: Preliminary report with the provisional assessments is expected in the 3rd quarter of 2011. At present, essential information and specifications of the methodical approach are still missing. Each of these steps yields considerable methodological challenges and can significantly influence the results of the cost-benefit analysis. The MTC method, in particular, must be transparently described. Only in this manner, will it be possible to prevent uncertainties after every step from adding up to an invalid overall result. CONCLUSIONS:  When MTC do not present relevant differences, or present them inadequately, this has significant effects on the assessment of therapeutic superiority, as well as on the appropriateness of the costs within the scope of the cost-benefit analysis. The result of such a cost-benefit analysis would be that the benefits and additional benefits of new drugs are levelled and the price level for modern antidepressants is decreased for Germany in future.