OBJECTIVES: To investigate, through a prospective follow-up study, the effects of a dietary supplementation challenge in men with isolated high-grade prostatic intraepithelial neoplasia (HGPIN). METHODS: The effects of a 6-month supplementation challenge with selenium, vitamin E, and soy isoflavonoids in men diagnosed with isolated HGPIN on biopsy were evaluated. A total of 100 patients entered the study. Of the 100 men, 29 were excluded because they refused additional biopsies or were noncompliant with the protocol, 71 underwent repeat biopsies at 3 months, and 58 underwent a third set at 6 months. The prostate-specific antigen (PSA) level was recorded at inclusion and before each set of biopsies. The study endpoint was defined as the diagnosis of PCa at 3 months or the histopathologic status at 6 months. RESULTS: At the study endpoint, PCa had been found in 24 men (33.8%), HGPIN in 34 (47.9%), and no HGPIN or carcinoma in 13 (18.3%). The PCa risk throughout the study period was 25.0% in the group with a stable or decreasing PSA level (n = 48, 67.6%) and 52.2% in the group with an increasing PSA level (n = 23, 32.4%). This difference was statistically significant (P = 0.0458). Isolated HGPIN remaining at the first repeat biopsy and the percentage of initial cores with HGPIN were significant predictors of PCa at additional biopsies. CONCLUSIONS: The results of our study have shown that a decrease in the PSA level while taking a selenium, vitamin E, and soy isoflavonoids supplement predicts for a significantly lower risk of PCa in future biopsies. The percentage of initial biopsy cores with HGPIN and isolated HGPIN remaining at the first repeat biopsy are significant predictors of PCa in future biopsies.