Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Signet-ring cell carcinomas (SRCCs) tend to present at higher stages and thus are generally associated with a worse prognosis. It has been postulated that a deficiency of E-cadherin may be causal in the pathogenesis of SRCC in animal models. In this study, we systemically analyzed the expression of E-cadherin and β-catenin, a key component of the cadherin complex, in 137 consecutive SRCCs of various organ systems to explore the significance of these molecules in the pathogenesis and progression of SRCCs. Seventy-six percent of SRCCs showed loss or reduced E-cadherin expression. Aberrant β-catenin expression, defined as loss of membranous expression and nuclear/cytoplasmic subcellular localization, was observed in 60% of these cases, with the altered β-catenin expression observed most commonly in the breast (93%) and least in the lung (38%) primaries. Further, the aberrant β-catenin was significantly associated with pathologic nodal stage (P=0.002) and clinical stage (P=0.02). Our findings demonstrated that reduced membranous E-cadherin and aberrant β-catenin expression were frequent events in SRCCs of various organs, and that the altered β-catenin expression was significantly associated with advanced disease. The observations further support the importance of these molecules in the pathogenesis of SRCCs, and indicate the fundamental role of the Wnt/β-catenin signaling pathway in the progression of these tumors. Further investigations of the downstream molecules in this cascade may provide potential novel therapeutic targets for this aggressive tumor type.