Background Docetaxel is an established first-line therapy to treat metastatic castration-resistant prostate cancer (mCRPC). Recently, abiraterone and cabazitaxel were approved for use after docetaxel failure, with improved survival. National Institute for Health and Clinical Excellence (NICE) preliminary recommendations were negative for both abiraterone (now positive in final recommendation) and cabazitaxel (negative in final recommendation). Objective To evaluate the cost-effectiveness of abiraterone, cabazitaxel, mitoxantrone and prednisone for mCRPC treatment in US. Methods A decision-tree model was constructed to compare the two mCRPC treatments versus two placebos over 18 months from a societal perspective. Chance nodes include baseline pain as a severity indicator, grade III/IV side-effects, and survival at 18 months. Probabilities, survival and health utilities were from published studies. Model cost inputs included drug treatment, side-effect management and prevention, radiation for pain, and death associated costs in 2010 US dollars. Results Abiraterone is a cost-effective choice at 94K/QALY(qualityadjustedlifeyears)comparedtoplaceboinourbase-caseanalysis.Cabazitaxelandabirateronearethemosteffective,yetalsomostexpensiveagents.Theincrementalcost-effectivenessratios(ICER)atbase-caseare 101 K/QALY (extended dominated) for mitoxantrone vs. placebo, 91K/QALYforabirateronevs.mitoxantrone, 956 K/QALY for cabazitaxel vs. abiraterone. Abiraterone becomes less cost-effective as its AWP increases, or if the cost of mitoxantrone side-effect management decreases. Increases in the percentage of patients with baseline pain leads to an increased ICER for both mitoxantrone and abiraterone, but mitoxantrone does relatively better. Cabazitaxel remains not cost-effective. Conclusion Our base case model suggests that abiraterone is a cost-effective option in docetaxel-refractory mCRPC patients. Newer treatments will also need a CEA assessment compared to abiraterone.