Prostate specific antigen (PSA) is a protein produced both by normal cells in the prostate and by prostate cancer cells. For men who have had prostate cancer, monitoring PSA levels can provide an early indication of recurrence of the disease. Naturally-occurring plant compounds, known as phytochemicals, may play a role in prostate cancer prevention, risk of recurrence, and therapy. This phase 1 trial evaluated the effects of white button mushroom (WBM) powder on PSA levels and determined the tolerability and biological activity of WBM. The 36 patients enrolled in this trial had previously undergone surgery and/or radiation treatment for prostate cancer and subsequently were found to have a continuously rising PSA level. Patients were given tablets containing WBM powder at doses from 4g to 14g (equivalent to 40g to 140g of fresh WBM). The mean reduction in PSA levels was 11%. Two patients receiving 8 and 14 g/d demonstrated complete response: their PSA declined to undetectable levels that continued for 49 and 30 months. Two patients who received 8 and 12 g/d experienced partial response: a decline of at least 50% in PSA levels. After 3 months of therapy, 13 (36%) patients experienced some PSA decrease below baseline. PSA levels remained stable in 5 patients. Patients who responded had higher levels of a cytokine called interleukin-15 (IL-15) at the beginning of this study, and experienced a decline in immuno-suppressive myeloid-derived suppressor cells (MDSCs) during the study. When comparing responders to non-responders, the following factors did not seem to affect the response: the daily mushroom dose, grade of cancer, baseline PSA level, weight, age, baseline testosterone levels and type of prior therapy. WBM powder therapy did not influence the levels of circulating androgen hormones: testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA). The authors concluded that therapy with WBM appears to impact PSA levels and decrease immunosuppressive factors. Future trials should contain a placebo group and more research is needed to isolate the compound(s) from the WBM with anti-prostate cancer activity.