OBJECTIVES: To evaluate cost-effectiveness of abiraterone and cabazitaxel compared to existing palliative chemotherapy, mitoxantrone and placebo for metastatic castration-resistant prostate cancer (mCRPC) patients; focusing on differences in baseline illness severity. METHODS: A decision tree comparing four treatment strategies in mCRPC patients over an 18-month-period was constructed from the societal perspective. Chance nodes included baseline pain as a severity indicator, grade III & IV neutropenia or cardiac events, and survival at 18 months. Probabilities and life expectancies were from two clinical trials (COU-AA1 and TROPIC2). Costs in 2010 US dollars included drugs (Redbook), physician visits, procedures, tests (CPT-codes) and hospitalizations (HCUP). Model cost inputs included drugs, chemotherapy administration, adverse events management, radiotherapy for pain palliation, and death. The short duration excluded need for discounting. Utilities for bone pain, neutropenia, cardiac events and radiation therapy were from published sources. Baseline severity was altered to reflect relatively ill populations. RESULTS:  Cabazitaxel and abiraterone give the best effects and cabazitaxel is most costly. For mitoxantrone as compared with placebo, the incremental cost effectiveness ratio (ICER) was $110K/QALYS and $63K/LYS. For abiraterone versus mitoxantrone, the ICER was $76K/QALYS and $52K/LYS. Cabazitaxel has an ICER of $925K/QALYS and $378K/LYS compared to abiraterone. One-way and probabilistic sensitivity analyses show a robust model for most variables. This remained so across the majority of WTP thresholds shown in acceptability curves and net monetary benefit calculations. Sensitive variables include abiraterone costs and neutropenia costs of mitozantrone. Even assuming most patients are severely ill to match sites with sicker populations, the relative cost-effectiveness does not change; abiraterone favored and cabazitaxel always above tolerable thresholds. CONCLUSIONS: Abiraterone is the most cost effective given WTP of $100,000. Despite slightly higher survival with cabazitaxel, it is never cost-effective with high drug and neutropenia costs. Even for care sites with relatively ill patients, abiraterone remains cost-effective.