Background: To evaluate the role of computed tomography (CT)-guided needle biopsy and sodium iodide fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in the investigation of solitary pulmonary nodules (SPN), which are discovered on screening chest radiographs, and to determine the cost-effectiveness of these modalities. Material/Methods: We have used decision-tree analysis models to assess the accuracy and cost-effectiveness of four strategies for the diagnosis and management of SPNs: CT alone strategy (baseline), CT plus FDG-PET strategy, CT plus FDG-PET plus CT-guided needle biopsy strategy, and CT plus CT-guided needle biopsy strategy. Reported values of prevalence of cancer, and sensitivity and specificity of each diagnostic modality were applied to the decision-tree models using Japanese health care costs. Results: The prevalence of lung cancer among SPNs discovered on the lung cancer screening was less than 10%. In this prevalence, the strategies using CT-guided needle biopsy were the cost-effective alternatives to the CT alone strategy (cost saving was Y436,470 - Y456,478 per patient), and had higher accuracies (95-96% vs. 67%). Both effects were mainly the result of reducing the number of the candidates who undergo unnecessary thoracotomy for a benign SPN, and these results were true over a wide range of prevalence of cancer (0-55%). The cost saving and accuracy of the CT plus FDG-PET strategy (159,206 and 92%) were approaching to those of the strategies using CT-guided needle biopsy. Conclusions: The introduction of CT-guided needle biopsy and FDG-PET for the evaluation of SPNs, which are discovered on screening chest radiograph, is potentially cost-effective in Japan with high accuracy.