OBJECTIVES: Pharmacoeconomic evaluations are more critical in developing countries in which economic effects of new and expensive therapies have significant impact on patients, insurance companies and the health systems. Since cost-effectiveness studies are too costly and time consuming, in these countries new medications are often being used in daily practice before being well documented as cost-effective interventions. This would force health organizations to perform comparative studies as alternatives to cost-effectiveness analysis. Trastuzumab, an anti-cancer monoclonal antibody which was approved by FDA in 1998, is an expensive medicine introduced to the Iranian pharmaceutical market since 2003, with an annual usage cost of 308,352,730,640 Rials ($ US 25,000,000) in 2010. METHODS: A systematic review on electronic medical databases including the Cochrane, CRD, EMBASE, HEED, MEDLINE, and PubMed, covering the years 2000 to 2009, was performed using relevant key words to extract publications investigating cost-effectiveness and efficacy of trastuzumab in breast cancer treatment. The Incremental Cost-Effectiveness Ratios (ICERs) were compared with a criterion introduced by WHO. RESULTS: The reported ICERs were between $90,118/QALY to $217,264/QALY and $13,361/QALY to $65,250/QALY in metastatic and adjuvant breast cancer therapy, respectively. The metastatic ICERs were 8 to 20 folds of the GDP per Capita in Iran whereas the adjuvant phase ICERs were 1.2 to 6 folds of it. Sensitivity analysis showed the results are more sensitive to discount rate, drug regimen cost, duration of survival benefits, as well as the risk of relapse and metastasis. CONCLUSIONS: Trastuzumab therapy in metastatic breast cancer cannot be cost effective in Iran, however as adjuvant therapy it is still a challenging issue. Unlimited access to this medicine would not be rational and recommendations with an approach to optimize its usage, e.g. administration in younger patients with poor prognosis and higher risk of relapse or using clean rooms to reduce drug wasting, are strongly advised.