Although prostate cancer has become the most common solid tumor diagnosed in men and the second leading cause of death due to malignancy, the progression of the disease is still somewhat unpredictable, until it becomes locally advanced or metastatic. The clinical problem to distinguish between dormant and progressive cancers is essential to patient care, as surgical and medical therapies have significant risk of morbidity and disability. Multiple gene expression in prostate cancer was surveyed by differential display cloning between the undifferentiated hormone refractory human prostate cancer cell line PC-3 (highly tumorigenic in nude mice) the hormone responsive LNCaP cell line (weakly tumorigenic in nude mice), and the poorly differentiated DU-145 cell line (moderately tumorigenic). ApoE mRNA was found to be highly expressed only in PC-3 cell-line. We further examined its protein expression by immunohistochemistry in 20 prostatectomy specimens and an association between Gleason score for each sample and ApoE expression was determined. ApoE expression correlates directly with the Gleason score in tissue sections, hormone independence as well as local and distant invasiveness. Prostatic intraepithelial neoplasias (PINs) adjacent to clinically manifested cancer were positive whereas more distant PINs were negative for ApoE. ApoE may represent a marker of more aggressive cells in human prostate cancers.