Background: Treatment response biomarkers are urgently needed for castration-resistant prostate cancer (CRPC). Baseline and post-treatment circulating tumor cell (CTC) counts of >= 5 cells/7.5 ml are associated with poor CRPC outcome. Objective: To determine the value of a >= 30% CTC decline as a treatment response indicator. Design, setting, and participants: We identified patients with a baseline CTC count >= 5 cells/7.5 ml and evaluable post-treatment CTC counts in two prospective trials. Intervention: Patients were treated in the COU-AA-301 (abiraterone after chemotherapy) and IMMC-38 (chemotherapy) trials. Outcome measures and statistical analysis: The association between a >= 30% CTC decline after treatment and survival was evaluated using univariable and multivariable Cox regression models at three landmark time points (4, 8, and 12 wk). Model performance was evaluated by calculating the area under the receiver operating characteristic curve (AUC) and c-indices. Results: Overall 486 patients (122 in IMMC-38 and 364 in COU-AA-301) had a CTC count >= 5 cells/7.5 ml at baseline, with 440, 380, and 351 patients evaluable at 4, 8, and 12 wk, respectively. A 30% CTC decline was associated with increased survival at 4 wk (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.36-0.56; p = 5 cells/7.5 ml and a 30% CTC decline had similar overall survival in both arms. Conclusions: A 30% CTC decline after treatment from an initial count >= 5 cells/7.5 ml is independently associated with CRPC overall survival following abiraterone and chemotherapy, improving the performance of a multivariable model as early as 4 wk after treatment. This potential surrogate must now be prospectively evaluated. Patient summary: Circulating tumor cells (CTCs) are cancer cells that can be detected in the blood of prostate cancer patients. We analyzed changes in CTCs after treatment with abiraterone and chemotherapy in two large clinical trials, and found that patients who have a decline in CTC count have a better survival outcome. (C) 2016 European Association of Urology. Published by Elsevier B.V.