Well-differentiated papillary mesothelioma is a pathologic entity distinct from malignant mesothelioma and has a different tumor biology highlighted by its relatively good prognosis. We report the case of a 27-year-old woman with pleural well-differentiated papillary mesothelioma, who was treated with bilateral pleurodesis and pericardial window to control the production of malignant fluid, without significant systemic anticancer treatment. She survived for 16 years, confirming its indolent nature. This case report also highlights the role of fluid cytology, immunohistochemistry, and electron microscopy in the diagnosis of well-differentiated papillary mesothelioma and the potential use of serum CA-125 as a marker of progression.