Intracranial gliomas and lymphomas may share similar radiological manifestations, while the treatment strategies for them are different. The aim of the study was to investigate the diagnostic value of fluorine-18-fluoro-2-deoxy-D-glucose (F-18-FDG) positron emission computed tomography (PET) for differentiation of multicentric gliomas and intracranial multiple diffuse large B-cell lymphomas (DLBCLs) as a study of diagnostic accuracy. A total of 32 patients with multiple intracranial tumors visualized on contrast-enhanced magnetic resonance imaging (MRI) were retrospectively evaluated. Histopathological findings confirmed multicentric gliomas and multiple DLBCLs in 17 and 15 patients, respectively. All patients underwent F-18-FDG PET with or without C-11-methionine PET. Maximum standardized uptake values (SUVmax) and tumor-to-normal tissue (T/N) ratios were compared between the 2 tumors. The diagnostic value of F-18-FDG PET for differentiating multicentric gliomas from multiple DLBCLs was evaluated by receiver operating characteristic (ROC) analysis. The SUVmax of multiple DLBCLs was significantly higher than that of multicentric gliomas (P=.009). However, the percentage of maximum difference-value of SUVmax (or T/N ratio) of multiple DLBCLs was significant lower than that of multicentric gliomas (P<.001). The ROC curve demonstrated that the percentage of maximum difference-value of SUVmax (or T/N ratio) on F-18-FDG PET images could effectively differentiate multicentric gliomas from multiple DLBCLs, with a cut-off value of 44.4%, sensitivity of 64.7%, and specificity of 100% (P<.001). Percentage of maximum difference-value of SUVmax (or T/N ratio) on F-18-FDG PET images might be a potential indicator for distinguishing multicentric gliomas from intracranial multiple DLBCLs, which might help determine the treatment strategy.