SummaryProlyl oligopeptidase (PREP) is a serine protease that hydrolyzes peptides shorter than 30-mer, and it has been connected with multiple physiological and pathological conditions. PREP has been mostly studied in the brain, but significant PREP activities have been measured in peripheral tissues. Moreover, increased PREP activities have been found in tumors. In this study, the authors studied the immunohistochemical distribution of PREP protein in human peripheral tissues and in ovarian and colorectal tumors. PREP was found to be widely distributed in human peripheral tissues and specifically in certain cells. The most intense PREP expression was seen in the testis, ovaries, liver, and some parts of the skin. At the cellular level, high PREP levels were seen as a rule in secreting epithelial cells and cells involved in reproduction. Increased PREP expression was seen in most of the tumors studied. PREP expression was higher in malignant than benign tumors, and in ovarian epithelial cancers, there was a trend for increased PREP staining with increased malignancy grade. Results suggest that PREP may be associated with secretory processes as well as in reproduction. A more abundant expression of PREP in malignant than benign tumors suggests that PREP may be associated with expansion and metastasis of tumors. (J Histochem Cytochem 60:706-715, 2012)