Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe disease with a poor prognosis. We aimed to determine if F-18-fluorodeoxyglucose (F-18-FDG) PET/CT-derived radiomic features alone or combination with clinical parameters could predict survival in adult HLH.Methods: This study included 70 adults with HLH (training cohort, n = 50; validation cohort, n = 20) who underwent pretherapeutic F-18-FDG PET/CT scans between August 2016 and June 2020. Radiomic features were extracted from the liver and spleen on CT and PET images. For evaluation of 6-month survival, the features exhibiting p < 0.1 in the univariate analysis between non-survivors and survivors were selected. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to develop a radiomics score (Rad-score). A nomogram was built by the multivariate regression analysis to visualize the predictive model for 3-month, 6-month, and 1-year survival, while the performance and usefulness of the model were evaluated by calibration curves, the receiver operating characteristic (ROC) curves, and decision curves.Results: The Rad-score was able to predict 6-month survival in adult HLH, with area under the ROC curves (AUCs) of 0.927 (95% CI: 0.878-0.974) and 0.869 (95% CI: 0.697-1.000) in the training and validation cohorts, respectively. The radiomics nomogram combining the Rad-score with the clinical parameters resulted in better performance for predicting 6-month survival than the clinical model or the Rad-score alone. Moreover, the nomogram displayed superior discrimination, calibration, and clinical usefulness in both the cohorts.Conclusion: The newly developed Rad-score is a powerful predictor for overall survival (OS) in adults with HLH. The nomogram has great potential for predicting 3-month, 6-month, and 1-year survival, which may timely guide personalized treatments for adult HLH.