Soy isoflavones sensitize prostate cancer cells to radiation therapy by inhibiting cell survival pathways activated by radiation. At the same time, soy isoflavones have significant antioxidant and anti-inflammatory activity, which may help prevent the side effects of radiation. Therefore, we hypothesized that soy isoflavones could be useful when given in conjunction with curative radiation therapy in patients with localized prostate cancer. In addition to enhancing the efficacy of radiation therapy, soy isoflavones could prevent the adverse effects of radiation. We conducted a pilot study to investigate the effects of soy isoflavone supplementation on acute and subacute toxicity (6 mo) of external beam radiation therapy in patients with localized prostate cancer. Forty-two patients with prostate cancer were randomly assigned to receive 200 mg soy isoflavone (Group 1) or placebo (Group 2) daily for 6 mo beginning with the first day of radiation therapy, which was administered in 1.8 to 2.5 Gy fractions for a total of 73.8 to 77.5 Gy. Adverse effects of radiation therapy on bladder, bowel, and sexual function were assessed by a self-administered quality of life questionnaire at 3 and 6 mo. Only 26 and 27 patients returned completed questionnaires at 3 and 6 mo, respectively. At each time point, urinary, bowel, and sexual adverse symptoms induced by radiation therapy were decreased in the soy isoflavone group compared to placebo group. At 3 mo, soy-treated patients had less urinary incontinence, less urgency, and better erectile function as compared to the placebo group. At 6 mo, the symptoms in soy-treated patients were further improved as compared to the placebo group. These patients had less dripping/leakage of urine (7.7% in Group 1 vs. 28.4% in Group 2), less rectal cramping/diarrhea (7.7% vs. 21.4%), and less pain with bowel movements (0% vs. 14.8%) than placebo-treated patients. There was also a higher overall ability to have erections (77% vs. 57.1%). The results suggest that soy isoflavones taken in conjunction with radiation therapy could reduce the urinary, intestinal, and sexual adverse effects in patients with prostate cancer.