Background: Ra-223 is an alpha emitter that selectively targets BM. Ra-223 is an approved treatment option for CRPC patients (pts) based on a significant improvement in overall survival. The pivotal phase III ALSYMPCA trial did not mandate monitoring of antitumor activity by imaging. We aimed to describe the imaging response in pts treated with Ra-223. Methods: Retrospective evaluation of computed tomography (CT) and bone scintigraphy (BS) of consecutive CRPC pts treated with Ra-223. All patients had scans done at baseline. Patients were treated with Ra-223 in 8 centers across 3 countries. Therapy consisted of standard Ra-223 administration (50 kBq q4 weeks for up to 6 injections). Results: A total of 127 pts were included (median age 72), of which 68% (n = 86) were treated with Ra-223 post docetaxel chemotherapy. A total of 20% (n = 26) of patients received concomitant abiraterone or enzalutamide. 52% (n = 66) patients completed the planned 6 injections. Clinical benefit (improvement of skeletal pain and/or performance status) was noted in 48% (n = 40/83 pts with available data). Among 82 pts with available data, a transient increase in bone metastases related pain occurred in 33% (n = 27). Among 101 patients with BS data available at 3 months, stable disease (equal or less than 1 new lesion) was noted in 71% (n = 72), and 2 or more new lesions in 28% (n = 28). Among 72 patients with BS available at 6 months, stable disease was documented in 93% (n = 67), and progression with at least 2 new lesions versus the 3 months status in only 7% (n = 5) pts. Among 96 patients with available CT data, soft tissue progression during therapy was noted in 40% (n = 38), this progression was found in lymph nodes only in 61% (n = 23) and as progressive disease in lymph node and/or visceral (lung, liver, adrenal) metastases in 55% (n = 21). Conclusions: Progression as per PCWG2 criteria of BM during Ra-223 was uncommon. A bone flare (pain and radiological) may be noted during the first 3 months, and should not be confused with progression. A significant number of patients had soft tissue progression on therapy with Ra-223 supporting the rationale for combination trials.