Malignant pleural mesothelioma (MPM) increases the risk of venous thromboembolic (VTE) events. This risk is higher following extrapleural pneumonectomy (EPP) as part of trimodality therapy, where VTE can be catastrophic. In our series, the impact of warfarin in preventing a pulmonary embolus (PE) after neoadjuvant chemotherapy and EPP for MPM was analysed. A retrospective analysis of 21 consecutive patients undergoing EPP for MPM was conducted. The first 10 patients (Group A) had VTE prophylaxis by subcutaneous enoxaparin and compression stockings commenced a day prior to surgery, intraoperative pneumatic calf compression and early post-operative mobilization. Enoxaparin was continued for 30 days postoperatively. The following 11 patients (Group B) had the same VTE prophylaxis, together with warfarin, started prior to hospital discharge and continued for 6 months postoperatively. All patients had a computed tomography pulmonary angiogram within 8 weeks after surgery and a full examination at 1, 3, 6 and 12 months. Both groups were comparable for characteristics. Three patients in Group A suffered a PE at 4, 6 and 16 weeks postoperatively. One PE was fatal. No patient in Group B suffered VTE (P = 0.05, χ(2) test) or haemorrhagic complications. Warfarin anticoagulation following EPP is feasible and safe, and is associated with a significant reduction in VTE complications.