Malignant pleural mesothelioma is on a continuous rise throughout the Western countries. It is associated with asbestos fibre exposition in the past. Surgical approaches include extrapleural pneumonectomy and pleurectomy/decortication (PyD). We investigated the feasability of the implementation of cold-plasma coagulation (CPC) on the pleura, pericardium and diaphragm into an established therapeutic algorithm consisting of PyD and hyperthermic intrathoracal chemoperfusion (HITHOC) therapy. The underlying rationale was the prevention of cardiotoxic effects during HITHOC as well as accidental translocation of malignant cells to the abdomen. CPC was done as part of a multimodal therapy in stage III mesothelioma patients. Histologic examinations of pleural excisates after CPC were done. The patients were followed up in three-month intervals. Neither parenchymal fistulas, nor cardiotoxic effects were observed. The histologic examination of the pleural excisates showed complete predictable necrosis. Moreover, until now (median time after operation 1 year) no relapse of the disease was observed. CPC proved to be a safe technique when used on the pleura, pericardium and diaphragm. We consider our trial as a pilot-study. To evaluate potential survival benefits using this technique larger trials are mandatory.