We aimed to investigate the role of positron emission computed tomography (PET/CT) with ¹⁸F-choline for predicting the outcome of metastatic castration-resistant prostate cancer (mCRPC) submitted to treatment with Radium-223 (²²³Ra-therapy). Clinical records of 20 mCRPC patients submitted to PET/CT with ¹⁸F-choline before ²²³Ra-therapy were retrospectively evaluated. The following PET-derived parameters were calculated: number of lesions, maximum and mean standardized uptake values (SUVmax, SUVmean), lean body mass corrected SUV peak (SULpeak), metabolic tumor volume (MATV), and total lesion activity (TLA). After ²²³Ra-therapy, all patients underwent regular follow-up until death. The predictive power of clinical and PET-derived parameters on overall survival (OS) was assessed by Kaplan–Meier analysis and the Cox proportional hazard method. All the patients showed ¹⁸F-choline-avid lesions at baseline PET/CT. Among the enrolled subjects, eleven (55%) completed all the six scheduled cycles of ²²³Ra-therapy; seven (35%) were responders according to imaging and biochemical parameters. Mean OS was 12.7 ± 1.4 months: by Kaplan–Meier analysis, number of lesions, PSA level and TLA were significantly correlated with OS. In multivariate Cox analysis, TLA remained the only significant predictor of survival (p = 0.003; hazard ratio = 7.6, 95% confidence interval = 1.9–29.5 months). ¹⁸F-choline PET may be useful for patients’ stratification before ²²³Ra-therapy. In particular, high metabolically active tumor burden (i.e., TLA) was predictive of poor outcome.