Surgical resection is not feasible in most cases of malignant mesothelioma and palliation of symptoms remains the mainstay of treatment. When a pleural effusion is loculated, the standard treatment methods of intercostal tube drainage and pleurodesis may not be helpful. We report a 49-year-old man with malignant mesothelioma in whom intrapleural fibrinolysis was performed using streptokinase. It was successful in breaking the locules and draining the effusion. Intrapleural fibrinolysis should be considered in cases of loculated pleural effusion due to malignant mesothelioma, as it may provide symptom relief and palliation.