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Introduction and objective Sentinel lymph node biopsy (SLNB) is the most useful tool for node staging in melanoma. SLNB facilitates selective dissection of lymph nodes, that is, the performance of lymphadenectomy only in patients with sentinel nodes positive for metastasis. Our aim was to assess the cost of SLNB, given that this procedure has become the standard of care for patients with melanoma and must be performed whenever patients are to be enrolled in clinical trials. Furthermore, the literature on the economic impact of SLNB in Spain is scarce. Method From 2007 to 2010, we prospectively collected data for 100 patients undergoing SLNB followed by transhilar bivalving and multiple-level sectioning of the node for histology. Our estimation of the cost of the technique was based on official pricing and fee schedules for the Spanish region of Murcia. Results The rate of node-positive cases in our series was 20%, and the mean number of nodes biopsied was 1.96; 44% of the patients in the series had thin melanomas. The total cost was estimated at between €9486.57 and €10 471.29. Histopathology accounted for a considerable portion of the cost (€5769.36). Discussion The cost of SLNB is high, consistent with amounts described for a US setting. Optimal use of SLNB will come with the increasingly appropriate selection of patients who should undergo the procedure and the standardization of a protocol for histopathologic evaluation that is both sensitive and easy to perform.