Expansion of the lung is necessary for successful pleurodesis therapy in patients with malignant pleural effusion (MPE). However, this is often impossible in multiloculated MPEs. The aim of this study was to investigate the effect of the fibrinolytic agent, streptokinase, on pleurodesis therapy used in the management of multiloculated MPE. Forty patients with multiloculated MPEs were randomly assigned to two groups: fibrinolytic and control. In the fibrinolytic group, 250,000 IU of streptokinase in 50 ml saline was applied into the pleural space at 24-36-48-60 h after opening a tube thoracostomy. In the control group, the same procedure was carried out using only 50 ml saline solution. Both groups were compared based on the following: (1) volume of pleural drainage at 24-48, 48-72, and 24-72 h, (2) chest computer tomography images before and after therapy, (3) dyspnea symptoms after therapy, and (4) recurrence rate. The mean drainage volumes for the fibrinolytic and control groups were 493 and 248 cc at 24-48 h, 446 and 198 cc at 48-72 h, and 939 and 446 cc at 24-72 h (P < 0.001). Comparison of the two groups by computer tomography revealed that 17 patients (85 %) in the fibrinolytic group had greater than 40 % improvement, whereas only 7 patients (35 %) in the control group had the same degree of improvement (P = 0.001). The dyspnea symptoms disappeared in 90 % of the patients in the fibrinolytic group and in 55 % of the patients in the control group (P = 0.03). Recurrence rate was 11 % in fibrinolytic group and 45 % in control group (P = 0.07). Streptokinase is a reliable treatment option in obtaining effective pleural drainage and increasing lung expansion in patients with multiloculated MPE.