High-grade gliomas are brain tumors associated with a devastating prognosis. Recent studies have indicated that the combined use of amino acid PET and MRI is superior to MRI alone to plan the surgical resection of high-grade gliomas. The aim of the study was to analyze the cost-effectiveness of the use of amino acid PET for the surgical resection of high-grade gliomas, compared with MRI alone, from the perspective of the national health insurance in Germany. Methods: A decision-tree model was set up to compare 2 strategies: the use of MRI alone and the combined use of MRI and PET for surgical resection of high-grade gliomas. For the analysis, 2 scenarios were calculated: a baseline scenario and a more expensive scenario, accounting for disease severity. To test the robustness of the results, probabilistic sensitivity analyses using Monte Carlo simulation were calculated. Results: Compared with MRI alone, the combined use of MRI and PET showed an incremental cost-effectiveness ratio of €2,948 (€1~U.S.$1.3)per life-year gained for the baseline scenario and an incremental cost-effectiveness ratio of €4,105 per life-year gained for the admissible-charge-rate scenario. In the probabilistic sensitivity analysis in about 60% of the iterations, the combined use of PET and MRI was superior to MRI alone when assuming a willingness-to-pay threshold of €30,000. Conclusion: The model indicates that the combined use of MRI and PET may be cost-effective. The results of this analysis have to be considered carefully because there was only limited empiric evidence for several input parameters.