PURPOSE: To evaluate the incidence of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) in an initial 21-core extended biopsy scheme and to determine the prostate cancer detection rate in the repeated biopsy. METHODS: Between 2002 and 2008, 2,006 patients underwent a first 21-core extended biopsy scheme. Incidences of cancer, ASAP and HGPIN were studied. Cancer detection rate in the repeated 21-core extended biopsy for ASAP and HGPIN was reported and compared with those obtained on repeated biopsy for clinico-biological indications. RESULTS: Incidences of HGPIN and ASAP were 1.7 and 1.1%, respectively. The 6-core and 12-core biopsy schemes detecting HGPIN would have missed the diagnosis of cancer in 10 and 3.6% of cases, compared to a 21-core biopsy protocol, respectively. The cancer detection rate on repeated biopsy for HGPIN was 19% and not significantly different compared with the detection rate on repeated biopsy for clinico-biological indications (16.8%, p = 0.77). Seven prostate cancers were found among the 17 re-biopsies for ASAP revealing a detection rate of 41.2% (p = 0.01). All detected cancers were organ confined. No clinico-pathological data were independent predictor of cancer on repeated biopsy. CONCLUSION: Our report demonstrates the different risk profiles for HGPIN and ASAP in a 21-core extended biopsy scheme. The presence of HGPIN does not imply a higher risk for cancer detection at immediate re-biopsy compared to other patients for whom repeated biopsies were indicated for increasing or persistently increased PSA levels. Repeated biopsy is warranted when ASAP is diagnosed because of a high risk of prostate cancer.