OBJECTIVES: Given the increased use of interventions of knowledge translation to change clinical practice, it is necessary to evaluate their effectiveness and cost-effectiveness. In this systematic review we synthesized scientific evidence on the cost-effectiveness of knowledge translation methods in health professionals. METHODS: We searched studies in MEDLINE and EconLit databases up to March 2010. Complete economic evaluations based on clinical trials of knowledge translation in primary and specialized healthcare were selected, if published in English, Spanish, German or Italian. The primary outcome was the incremental cost-effectiveness ratio. Quality of the economic evaluations was assessed by the check-list by Drummond et al. The extracted information was presented in text and tables. RESULTS: Eighteen economic evaluations met the inclusion criteria. The knowledge translation interventions were aimed at different areas, like prescription, diagnostics, treatment, counselling and clinical practice guidelines. Thirteen studies were cost-effectiveness analyses, and five were cost-utility analyses. The effectiveness measures used in the cost-effectiveness studies are mainly intermediate results, while the cost-utility studies use mainly the QALYs (quality-adjusted life years). The perspective mostly used was the one of healthcare system. Training/education is the intervention most frequently assessed followed by feedback, academic detailing, software support and distribution of educational materials; eight studies combined two or more methods. Most of the interventions are effective in knowledge translation, i.e. fulfil the function for which they have been designed. CONCLUSIONS: Although the scientific evidence suggests that the knowledge translation interventions are effective, most of them are relatively costly, and therefore less cost-effective. Those interventions that require less resources or can be applied in different areas at low cost, should be developed and implemented.