PURPOSE We aimed to evaluate the value of F-18-FDG positron emission tomography/computed tomography (PET/CT) for identifying the possible causes of secondary hemophagocytic lymphohistiocytosis (HLH). METHODS Forty-five cases (17 female, 28 male; age, 17-79 years) with secondary HLH were included. The standard of reference for diagnosis in all patients was a combination of histology, clinical results (medical history, physical examination, and laboratory test results), and follow-up imaging for at least 12 months. All cases underwent 18F-FDG PET/CT to identify the possible trigger in HLH. RESULTS Of 45 secondary HLH cases 10 (22.2%) were associated with infection, seven (15.6%) with rheumatic disease, and 28 (62.2%) with lymphoma. PET/CT images of 22 secondary HLH cases (48.9%) showed true positive results. PET/CT images demonstrated obvious tracer uptake in five of 10 secondary HLH cases with infection, one of three cases with lupus, two of two cases with rheumatoid arthritis, one of two cases with adult-onset Still disease, and 13 of 28 cases with lymphoma. CONCLUSION PET/CT is helpful for identifying the possible trigger (infection or malignant disease) and extent of secondary HLH. However, PET/CT alone is not sufficient to make a correct differential diagnosis.