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Purpose: To perform a cost-effectiveness analysis of radium-223 plus Best Supportive Care (BSC) compared to BSC in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and without previous docetaxel treatment in Spain. Design and methods: A Markov model was developed to compare radium-223 versus BSC and to accrue the health outcomes and costs of a simulated cohort of mCRPC patients. Quality-adjusted life year (QALY) and life year (LY) were selected as health outcomes to measure the effectiveness of treatment alternatives. Main health resource use and efficacy inputs were obtained from a randomized controlled trial comparing radium-223 versus placebo. Unit costs were retrieved from Spanish databases and published sources. One-way and probabilistic sensitivity analyses were carried out to assess uncertainty. Results: Total costs and QALYs were €65 067 and 1.12 QALYs for radium-223 and €55 437 and 0.77 QALYs for BSC. Therefore, incremental costs per QALY were €27 606. The sensitivity analysis showed that with a willingness-to-pay threshold of €30 000 per QALY, radium-223 would have a probability of 48% of being cost-effective compared to BSC. Conclusions: Although results must be assessed with caution, from the Spanish National Health System perspective and based on the results of the present analysis, radium-223 could be a suitable option of health resources’ utilization for end of life mCRPC without previous docetaxel treatment, subject to a moderate level of uncertainty.