Purpose The purpose of this study was to investigate the prognosis predicting value of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of F-18-FDG PET/CT, and clinical inflammatory cytokines in newly diagnosed secondary hemophagocytic lymphohistiocytosis (SHLH). Methods We retrospectively collected 58 patients with newly diagnosed SHLH from August 2016 to July 2019 in our hospital. All patients were followed up between 6 and 24 months. First, a comprehensive comparison of the general data between the death and the survival group was performed. Clinical lab indexes included were recorded and analyzed retrospectively. Second, the correlation between F-18-FDG PET/CT semiquantitative metabolic parameters of VAT, SAT and inflammatory cytokines was performed. 3D slicer software was used to get SUV and volume of VAT and SAT from F-18-FDG PET/CT. Third, overall survival (OS) analysis was performed. Finally, the prognosis predicting model was built based on risk factors to stratify SHLH patients. Results There was significant difference in WBC, PLT, FBG, IL-10, PCR tests of EBV-DNA loads, SCD25 between the death group and the survival group. There was significant correlation between SAT coefficient variance (CV) and CRP, the mean standardized uptake value (SUVmean) of SAT (SAT SUVmean) and TG, SAT SUVmean and ESR. In univariate analysis with Cox regression analysis, SUVmean of VAT (VAT SUVmean), SAT Volume, SUVmean of SAT, CV of SAT (SAT HU CV), plasma EBV-DNA, WBC, PLT, FBG showed significance with OS. In multivariate Cox regression analysis, SAT Volume, SUVmean of SAT, plasma EBV-DNA, were independent prognostic factors for OS. Conclusions For newly diagnosed SHLH, SAT Volume, SUVmean of SAT, plasma EBV-DNA had significant relationship with poor prognosis. They were important independent predictors for overall survival for newly diagnosed SHLH.