Most studies on the risk of cancer after high-grade prostatic intraepithelial neoplasia (PIN) on biopsy have been small (fewer than 100 men), have not analyzed in detail if histologic features can predict cancer, and have not assessed the risk of cancer with multiple repeat biopsies. We analyzed 245 men in whom the only abnormal finding on the initial biopsy was high-grade PIN and who had at least one follow-up biopsy. Repeat biopsy identified cancer in 32.2% of men. If only one follow-up biopsy had been performed on the 245 men, only 24.5% of men would have been found to have cancer. The only independent histologic predictor of a cancer diagnosis was the number of cores with high-grade PIN; risk of cancer: 30.2% with 1 or 2 cores, 40% with 3 cores, and 75% with >3 cores. The following did not predict cancer: number of high-grade PIN glands, maximum percentage of gland involved by high-grade PIN, nucleolar prominence, percentage of cells with prominent nucleoli, pattern of high-grade PIN (flat, tufting, micropapillary, cribriform), marked pleomorphism, digital rectal examination, transrectal ultrasound findings, family history of prostate cancer, serum prostate specific antigen (PSA) at time of high-grade PIN diagnosis, and rate of change of serum PSA. Eighty-one (33%) men had more than one follow-up biopsy; in these cases the following findings on the original high-grade PIN biopsy predicted cancer: the presence of mitoses, the number of positive cores, predominant micropapillary and cribriform high-grade PIN, and very large prominent nucleoli. Of 81 men with more than one follow-up biopsy, if the first repeat biopsy were benign, high-grade PIN, or atypical, the eventual cancer rate was 10%, 25.9%, and 57.1%, respectively (p = 0.002). Of 15 men with more than two repeat biopsies, only two (13.3%) had cancer. In summary, approximately one third of men with high-grade PIN on biopsy have cancer on follow-up. If cancer is not found on the first two follow-up biopsies, it will unlikely be found. Although clinical findings at the time of diagnosis of high-grade PIN are not useful to predict who might have cancer, histologic findings may help identify who needs additional biopsies.