Background and Objective <p>The diagnosis of infectious diseases is often a challenging problem faced by clinicians, especially in the case of complex infections manifested as fever of unknown origin or inflammation of unknown origin (FUO/IUO). Currently, ¹⁸F-fluorodeoxyglucose (FDG) Positron emission tomography/Computed tomography (PET/CT) has been increasingly used in the inflammatory diseases. This study aimed to explore the diagnostic and therapeutic value of FDG PET/CT for infectious diseases in patients with FUO/IUO.</p> Methodology <p>A retrospective analysis was conducted on the clinical and imaging data of 156 consecutive hospitalized patients who underwent FDG PET/CT examination due to the etiological diagnosis of FUO/IUO and were ultimately diagnosed with infectious diseases. The analysis included general clinical characteristics and pathogenic distribution among patients. FDG PET/CT imaging results were evaluated, encompassing overall lesion detection rates in the cohort, detection efficacy for infectious foci caused by different types of pathogens, and FDG uptake patterns in lesions. The correlation between FDG PET/CT findings and serum inflammatory markers was assessed. Additionally, the impact of FDG PET/CT results on clinical diagnosis and treatment was evaluated through clinical questionnaires.</p> Results <p>Among the 156 patients with infectious diseases, 82 cases (52.6%) obtained etiological evidence, including 51 cases of bacterial infection, 13 cases of viral infection, 5 cases of other rare pathogens infection, and 13 cases of mixed infection. The remaining 74 cases without pathogen evidence were confirmed to be effective in antimicrobial therapy through clinical follow-up. In FDG PET/CT imaging, abnormal FDG uptake was observed in 139 cases (89.1%), among which infection foci were detected in 100 cases (64.1%). The detection rate of mixed pathogen infection lesions by FDG PET/CT was significantly higher than that of viral infection lesions (χ2 = 6.500; P = 0.011). Infections with different types of pathogens could involve multiple organs and tissues throughout the body, and there was no significant difference in the distribution of infection foci. There was no significant difference in the degree of FDG uptake in infection foci, liver, spleen, and bone marrow among different types of pathogens. There were statistical differences in the levels of serum CRP, WBC, NE%, NEUT#, LY%, LYMP# and LDH among the patients with detected infection foci by FDG PET/CT, patients manifested as non-specific inflammatory uptake, and patients with negative PET/CT (all P &lt; 0.05). Clinical questionnaire results showed that FDG PET/CT was helpful in the initial etiological diagnosis for 100 patients (64.1%); 33 patients (21.2%) obtained etiological evidence through biopsy at the site indicated by PET/CT; and the treatment plan was changed after FDG PET/CT examination in 68 patients (43.6%).</p> Conclusion <p>For complex infectious diseases in FUO/IUO, FDG PET/CT can not only help detect infectious foci, indicate appropriate biopsy sites and assist in obtaining etiological evidence, but also provide key information for the establishment of clinical treatment plans.</p>