Myelin protein zero-like 3 (MPZL3) is an immunoglobulin-containing transmembrane protein with predicted cell adhesion molecule function. Loss of 11q23, in which the MPZL3 gene resides, is frequently observed in cancer. Yet the role and consequences of altered MPZL3 expression have not been explored in tumor development and progression. We addressed this in ovarian cancer, in which both MPZL3 amplification and deletions are observed in respective subsets of high-grade serous specimens. Whereas high and low MPZL3-expressing populations are similarly observed in primary ovarian tumors from an independent patient cohort, metastatic omental tumors largely display decreased MPZL3 expression, suggesting that MPZL3 loss is associated with metastatic progression. MPZL3 knockdown leads to an increase in EMT gene expression in OVCAR4 and OVCA433 cell lines, a transcript signature that is associated with poor patient outcomes. MPZL3 promotes homotypic cancer cell adhesion, and decreasing MPZL3 expression enhances invasion and clearance of mesothelial cell monolayers. Conversely, MPZL3 loss abrogates cell-cycle progression and proliferation, with cells adopting senescence features. This was associated with decreased sensitivity to cisplatin and reduced DNA damage and apoptosis in response to treatment in OVCAR4 cells. Our study suggests that decreased expression of the predicted adhesion molecule MPZL3 is associated with low proliferation but increased metastatic potential during ovarian cancer tumor progression. SIGNIFICANCE: This work presents novel findings that decreased expression of the potential cell adhesion molecule MPZL3 is a phenotype of ovarian cancer progression and metastasis.