OBJECTIVES: A number-needed-to-treat (NNT) analysis comparing treatment with enzalutamide (ENZ) with abiraterone acetate plus prednisone (ABI+P) for chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) concluded that ENZA is cost-effective compared with ABI+P in a US setting. The analysis utilized the payer perspective and explored the incremental costs to achieve one additional patient free of radiographic progression, chemotherapy, or death over a 1-year time horizon. The analysis was adapted to Spain and the UK and estimated the difference in costs between therapies, respectively. METHODS: Differences in treatment patterns between countries were adjusted using locally sourced data from reimbursement and treatment guidelines; US unit costs were replaced with 2016 country-specific costs. Also, NNT and clinical outcomes were based on ENZ and ABI+P clinical trial data included in the original US analysis (Massoudi 2016). RESULTS: Total cost per treated patient for ENZ was lower than for ABI+P in both Spain (€34,610 versus €36,631) and the UK (£32,531 versus £32,669). Compared with ABI+P, treating 14 patients with ENZ resulted in one additional patient free of progression/death over 1 year at a cost saving of €28,879 (Spain) or £1962 (UK), treating 26 patients with ENZ resulted in one additional patient with chemotherapy delayed over 1 year (cost saving: Spain €53,199; UK £3615), and treating 91 patients with ENZ resulted in one additional patient surviving over 1 year (cost saving: Spain €183,777; UK £12,487). Thus, ENZ is less costly and more effective for all three outcomes. The models’ results suggest that ENZ potentially decreases the risk of disease progression and death and delays chemotherapy initiation in chemotherapy-naïve patients. Results were confirmed among multiple sensitivity analyses. CONCLUSIONS: Consistent with the original US analysis, results modeled here for Spanish and UK contexts also suggest that ENZ is cost-effective versus ABI+P for treating chemotherapy-naïve patients with mCRPC.