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Objective To determine whether an interim 18F-fluoride positron-emission tomography/computed tomography (PET/CT) study performed after the third cycle of radium-223 dichloride (223RaCl2) therapy is able to identify patients that will not respond to treatment. Materials and Methods We retrospectively reviewed 34 histologically confirmed cases of hormone-refractory prostate cancer with bone metastasis in patients submitted to 223RaCl2 therapy. All of the patients underwent baseline and interim 18F-fluoride PET/CT studies. The interim study was performed immediately prior to the fourth cycle of 223RaCl2. The skeletal tumor burden-expressed as the total lesion fluoride uptake above a maximum standardized uptake value of 10 (TLF10)-was calculated for the baseline and the interim studies. The percent change in TLF10 between the baseline and interim studies (%TFL10) was calculated as follows: %TFL10 = interim TLF10 - baseline TLF10 / baseline TLF10. End points were overall survival, progression-free survival, and skeletal-related events. Results The mean age of the patients was 72.4 ± 10.2 years (range, 43.3-88.8 years). The %TLF10 was not able to predict overall survival (p = 0.6320; hazard ratio [HR] = 0.753; 95% confidence interval [CI]: 0.236-2.401), progression-free survival (p = 0.5908; HR = 1.248; 95% CI: 0.557-2.797) nor time to a bone event (p = 0.5114; HR = 1.588; 95% CI: 0.399-6.312). Conclusion The skeletal tumor burden on an interim 18F-fluoride PET/CT, performed after three cycles of 223RaCl2, is not able to predict overall survival, progression-free survival, or time to bone event, and should not be performed to monitor response at this time.