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This study investigated the prognostic significance of metabolically active tumor volume (MATV) measurements applied to (18)F-fluorocholine PET/CT in castration-resistant prostate cancer (CRPC).(18)F-fluorocholine PET/CT imaging was performed on 30 patients with CRPC. Metastatic disease was quantified on the basis of maximum standardized uptake value (SUV(max)), MATV, and total lesion activity (TLA = MATV × mean standardized uptake value). Tumor burden indices derived from whole-body summation of PET tumor volume measurements (i.e., net MATV and net TLA) were evaluated as variables in Cox regression and Kaplan-Meier survival analyses.Net MATV ranged from 0.12 cm(3) to 1,543.9 cm(3) (median, 52.6 cm(3)). Net TLA ranged from 0.40 to 6,688.7 g (median, 225.1 g). Prostate-specific antigen level at the time of PET correlated significantly with net MATV (Pearson r = 0.65, P = 0.0001) and net TLA (r = 0.60, P = 0.0005) but not highest lesional SUV(max) of each scan. Survivors were followed for a median 23 mo (range, 6-38 mo). On Cox regression analyses, overall survival had a significant association with net MATV (P = 0.0068), net TLA (P = 0.0072), and highest lesion SUV(max) (P = 0.0173) and a borderline association with prostate-specific antigen level (P = 0.0458). Only net MATV and net TLA remained significant in univariate-adjusted survival analyses. Kaplan-Meier analysis demonstrated significant differences in survival between groups stratified by median net MATV (log-rank P = 0.0371), net TLA (log-rank P = 0.0371), and highest lesion SUV(max) (log-rank P = 0.0223).Metastatic prostate cancer detected by (18)F-fluorocholine PET/CT can be quantified on the basis of volumetric measurements of tumor metabolic activity. The prognostic value of (18)F-fluorocholine PET/CT may stem from this capacity to assess whole-body tumor burden. With further clinical validation, (18)F-fluorocholine PET-based indices of global disease activity and mortality risk could prove useful in patient-individualized treatment of CRPC.