Greater than 80% of all cancer cases are carcinomas, formed by the malignant transformation of epithelial cells. One of the key features of epithelial tumors is the presence of intercellular junctions, which link cells to one another and act as barriers to the penetration of molecules. This study assessed the expression of desmoglein-2, an epithelial junction protein, as a prognostic and diagnostic biomarker for ovarian cancer. Ovarian cancer sections were stained for DSG2 and signal intensity was correlated to cancer type and grade. DSG2 immunohistochemistry signals and mRNA levels were analyzed in chemo-resistant and chemo-sensitive cases. Ovarian cancer patient serum levels of shed DSG2 were correlated to disease-free and overall survival. Primary ovarian cancer cells were used to study DSG2 levels as they changed in response to cisplatin treatment. DSG2 expression was found to be positively correlated with cancer grade. Ovarian cancer patients with high serum levels of shed DSG2 fared significantly worse in both progression-free survival (median survival of 16 months vs. 26 months, p = .0023) and general survival (median survival of 37 months vs. undefined, p < .0001). A subgroup of primary chemotherapy-resistant cases had stronger DSG2 IHC/Western signals and higher DSG2 mRNA levels. Furthermore, our in vitro studies indicate that non-cytotoxic doses of cisplatin can enhance DSG2 expression, which, in turn, can contribute to chemo-resistance. We suggest that DSG2 can be used in stratifying patients, deciding on where to use aggressive treatment strategies, predicting chemoresistance, and as a companion diagnostic for treatments targeting DSG2.