Insulin-like growth factor binding protein 2 (IGFBP2) has been shown to be overexpressed in prostatic intraepithelial neoplasia (PIN) and invasive cancer and the serum level to parallel that of prostate-specific antigen (PSA) in prostate cancer. A combination of cDNA and tissue microarray results recently demonstrated overexpression of IGFBP2 in hormone refractory prostate cancer, indicating that the IGF system may be part of a key growth regulatory pathway in prostate cancer. The present study reexamines the immunohistochemical expression of IGFBP2 and its relationship to grade in tissue from 193 radical prostatectomy specimens from patients with localized prostate adenocarcinoma. We found a significant overexpression of IGFBP2 in all instances of PIN and in more than 90% of cancers regardless of the grade. An intense overexpression was noted in the neuroendocrine cells in normal glands as well as in cancer. The IGFBP2 expression was also analyzed in 18 cases of biopsy diagnosed prostate cancer. In all these cases, the glands interpreted as invasive cancer in hematoxylin-eosin stained sections overexpressed IGFBP2, without a significant correlation to grade. We conclude that overexpression of IGFBP2 is a powerful marker for malignant transformation in the prostate epithelium and suggest that optimized immunohistochemical detection of IGFBP2 expression may be an adjunct tool in the diagnosis of prostate cancer.