STAT3 mediated signaling pathways can be inhibited by PIAS3 (protein inhibitor of activated STAT3), which was recently found to regulate protein stability and function by its SUMO (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins. Over-expression of PIAS3 can induce apoptosis in prostate cancer cell lines both in vitro and in vivo. Checking endogenous PIAS3 expression in various human specimens by immunohistochemistry, we report that basal amounts of PIAS3 exist in the nucleus in a majority of epithelial and endothelial cells. Increased PIAS3 expression was observed in 100/103 samples examined in a variety of human cancers including lung, breast, prostate, colon-rectum, and brain tumors. Differential PIAS3 expression and the specific patterns may be useful as a molecular marker of human cancer.