AIM: To investigate the ability of combined 2-[F-18]-fluoro-2-deoxy-D-glucose (F-18-FDG) positron-emission tomography (PET)/computed tomography (CT) to determine potential causes of secondary haemophagocytic lymphohistiocytosis (sHLH) and to predict prognosis. MATERIAL AND METHODS: Forty-three patients (male/female 20/23, median age 48.5 years), who were diagnosed with sHLH and underwent FDG-PET/CT before treatment, were retrospectively reviewed. The clinical characteristics were compared to identify the predictors of high-yield FDG-PET/CT. Univariate and multivariate analyses were conducted to identify factors associated with survival. Statistical analysis was performed using SPSS version 19.0. RESULTS: PET results were helpful in 65.1% (28/43), whilst non-contributory in 34.9% (15/43) of patients with regard to the final diagnosis. Lymphoma was the most common (25/43) reason for sHLH, and patients with focal FDG uptake were more likely to be diagnosed with underlying diseases. C-reactive protein (CRP) was found to be a good indicator for the usefulness of PET/CT in HLH patients. Multivariate analysis showed that therapy regimen (hazard ratio [HR] = 4.99, p = 0.026), fibrinogen (FBG) < 1.5 g/l (HR = 3.87, p = 0.049) and spleen: mediastinum ratio (SP/M) (HR = 7.44, p = 0.006) were independent prognostic factors for survival. CONCLUSION: FDG-PET/CT could be a useful technique for detecting underlying diseases causing sHLH. CRP was a useful predictor of FDG-PET/CT effectiveness. Therapy regimen, FBG level, and SP/M were independent prognostic factors for HLH survival. (C) 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.