Purpose: Herbal therapies are unconventional treatments that have been used for several different diseases. PC-SPES is an herbal mixture, composed of eight different herbs (chrysanthemum, isatis, licorice, Ganoderma lucidum, Panax pseudo-ginseng, Rabdosia rubescens, saw palmetto, and scutellaria), which has been used as an alternative in the treatment of prostate cancer. We report two cases of hormone-refractory prostate cancer patients, who showed a favorable response to therapy with this herbal combination, controlling the progression of the disease. Methods: We report two cases of biopsy proven prostate cancer patients with metastatic disease, treated with total androgen blockade, progressing to an androgen-independent status. These patients were offered traditional therapies for hormone-resistant prostate cancer, and they chose to take PC-SPES. The follow-up as well as their evolution are described. Results: PC-SPES extract decreased the prostate-specific antigen (PSA) value for both patients from an initial value of 100 and 386 ng/mL to 24 and 114 ng/mL after 1 year and 4 months, respectively, remaining stable until now. No gynecomastia or hot flashes were observed in these patients and the treatment was well tolerated. Conclusion: PC-SPES has shown a strong estrogenic in vitro and in vivo activity as an alternative tool in the management of prostate cancer patients. These cases suggest that PC-SPES might have some potential activity against hormone-independent prostate cancers.