New biomarkers for metastatic prostate cancer are needed. The aim of this study was to evaluate the prognostic value of F-FDG PET whole-body tumor burden parameters in patients with metastatic prostate cancer who received first-line abiraterone or enzalutamide therapy. This was a retrospective study of patients with metastatic castration-sensitive prostate cancer (mCSPC, = 25) and metastatic castration-resistant prostate cancer (mCRPC, = 71) who underwent F-FDG PET/CT within 90 d before first-line treatment with abiraterone or enzalutamide at a tertiary-care academic cancer center. Whole-body tumor burden on PET/CT was quantified as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) and correlated with overall survival (OS) probabilities using Kaplan-Meier curves and Cox models. The median follow-up in survivors was 56.3 mo (interquartile range, 37.7-66.8 mo); the median OSs for patients with mCRPC and mCSPC were 27.8 and 76.1 mo, respectively ( < 0.001). On univariate analysis, the OS probability of mCRPC patients was significantly associated with plasma levels of alkaline phosphatase (hazard ratio [HR], 1.90; < 0.001), plasma levels of lactate dehydrogenase (HR, 1.01; < 0.001), hemoglobin levels (HR, 0.80; = 0.013), whole-body SUV (HR, 1.14; < 0.001), the number of F-FDG-avid metastases (HR, 1.08; < 0.001), whole-body metabolic tumor volume (HR, 1.86; < 0.001), and TLG (HR, 1.84; < 0.001). On multivariable analysis with stepwise variable selection, hemoglobin levels (HR, 0.81; = 0.013) and whole-body TLG (HR, 1.88; < 0.001) were independently associated with OS. In mCSPC patients, no significant association was observed between these variables and OS. In patients with mCRPC receiving first-line treatment with abiraterone or enzalutamide, F-FDG PET WB TLG is independently associated with OS and might be used as a quantitative prognostic imaging biomarker.