Hormone therapy for prostate cancer eventually fails leading to a stage called hormone-resistant (HR) disease. To investigate the issue about the characteristics and the radiation response in HR prostate cancer, we established HR cell sub-lines, 22RV1-F and 22RV1-DF, from 22RV1 cells with androgen deprivation for 16 weeks, and obtained LNCaP-HR from LNCaP with long-term bicalutamide treatment. We examined their sensitivities to radiation therapy and the underlying mechanisms. In vitro and in vivo faster tumor growth rate was noted in the HR prostate cancer cells when compared with control. Moreover, HR prostate cancer cells had greater capacity to scavenge reactive oxygen species, and suffered less apoptosis and senescence, and subsequently were more likely to survive from irradiation as measured by clonogenic assay in vitro and growth delay in vivo. The decreased p53 and increased mouse double minute 2 oncogene (MDM2) might be the potential underlying mechanisms for the more aggressive growth and more radioresistance in HR prostate cancer cells. In conclusion, HR prostate cancer cells appeared to be more aggressive in tumor growth and in resistance to radiation treatment. Regulation of the expressions of p53 and MDM2 should be the promising treatment strategies for relative radioresistant prostate cancer.