e17054 Background: The associations of antibiotics with overall survival (OS) and radiographic progression-free survival (rPFS) in trials in chemotherapy-naive metastatic castration-resistant prostate cancer remain unclear. Methods: COU-AA-302 (NCT00887198, n = 1088) and ACIS (NCT02257736, n = 982) patients were stratified by antibiotics administration. Since there was evidence of a threshold phenomenon, the association of duration of antibiotics administration and OS was assessed using a segmented linear regression model. Kaplan–Meier survival analysis was used to compare OS and rPFS. Hazard ratios were calculated using a multivariable Cox proportional-hazard model. Results: Using segmented linear regression models, we selected ≥30 days as the threshold for antibiotics administration in clinical trials. In COU-AA-302 Abiraterone + Prednisone (AAP) subgroup, antibiotics administration was associated with prolonged OS (50.4 vs. 33.8 months, HR0.57, 95%CI 0.38–0.84, P = 0.004) and prolonged rPFS (27.7 vs. 12.8 months, P = 0.0095). In COU-AA-302 Placebo + Prednisone (PLA) subgroup, antibiotics administration was also associated with prolonged OS (50.4 vs. 29.0 months, HR0.41, 95%CI 0.26–0.63, P < 0.001) and prolonged rPFS (16.46 vs. 5.72 months, P < 0.001). Antibiotics administration also improved patients’ outcomes in ACIS. In ACIS Apalutamide + Abiraterone + Prednisolone (AAAP) subgroup, antibiotics administration was associated with prolonged OS (43.3 vs. 27.3 months, HR0.68, 95%CI 0.54–0.85, P < 0.001) and prolonged rPFS (30.5 vs. 18.2 months, P < 0.001). In ACIS Placebo + Abiraterone + Prednisolone (PAAP) subgroup, antibiotics administration was also associated with prolonged OS (45.4 vs. 30.2 months, HR0.62, 95%CI 0.50–0.78, P < 0.001) and prolonged rPFS (23.4 vs. 13.4 months, P < 0.001). Conclusions: Within the limitations of post-hoc sub-analyses, antibiotics administration is associated with prolonged OS and rPFS in men with chemotherapy-naive metastatic castration-resistant prostate cancer. Further pharmacological researches and prospective clinical trials are needed to increase the indications for these drugs to benefit prostate cancer patients.