Diffuse malignant peritoneal mesothelioma (DMPM) is generally an understudied disease, largely because most molecular and clinical studies of mesothelioma have been conducted in patients with the more common malignant pleural mesothelioma. We present the case of a 45-year-old male that initially presented with abdominal discomfort and ascites. Diagnostic workup revealed advanced DMPM. Bimodal treatment was stared with cytoreductive surgery and hyperthermic intraperitoneal perfusion with chemotherapy procedure, followed by pemetrexed systemic monotherapy. After the disease progression, and because of a very good previous treatment response to pemetrexed, we decided to rechallenge systemic pemetrexed, along with the introduction of cisplatin. Although the intent behind systemic treatment was at first solely palliative, overall survival after the initial diagnosis was 50 months. Treatment based on rechallenging pemetrexed with or without cisplatin in patients with advanced DMPM can result in a quite satisfactory disease control and symptom management.