We report a case of progressive, multifocal melorheostosis in a 28-year-old woman, with involvement of the left arm, chest, spine, and impressive soft tissue involvement. In the past, she had undergone multiple vascular interventions. She presented with spontaneous massive bilateral chylothorax. After conservative treatment without success, we conducted bilateral pleurodesis. This resulted in a clear reduction of pleural effusions, but her medical condition subsequently worsened due to progressive parenchymatous infiltrates, and increased interlobal pleural effusions. She ultimately died of global respiratory insufficiency. In patients with melorheostosis, involvement of the soft tissue can result in distinctive morbidity, and whenever possible, treatment should be conservative.