Objective: To assess the safety and efficacy of hyperbaric oxygen (HBO) for treating radiation cystitis a long-term follow-up study was done in patients with prostate cancer, the second most common malignancy in Japan. Patients and Methods: A total of 38 patients at an age of 68 ± 8 years with radiation cystitis following irradiation of prostate cancer were treated with HBO at 2 absolute atmospheric pressures for 90 min daily. The average number of HBO treatment sessions in each patient was 62 ± 12. The follow-up period was 11.6 ± 3.7 years. We evaluated objective and subjective symptoms periodically with special reference to the initiation timing of HBO therapy. Results: High efficacy ratios of objective and subjective findings were obtained at 2 and 4 (79–95%) years, respectively. After 7 years’ follow-up, these ratios decreased slightly (72–83%) but still remained stable thereafter (75–88%) without any serious accident. Comparison of late morbidity scores before and 11.6 years after HBO therapy showed significant improvement (p < 0.0005). Twenty-eight patients (74%) obtained nonrecurrent outcome. They had received 18% lower (p < 0.001) radiation dosage than recurrent patients. The interval between the onset of hematuria and start of HBO treatment in nonrecurrent patients was 30% shorter (p < 0.001) than that of recurrent patients. Conclusions: We elucidated the long-term safety and beneficial effect of HBO therapy of radiation cystitis in patients with prostate cancer. Early application of HBO treatment after the onset of hematuria appears to produce favorable outcome.