A randomized phase III trial of bleomycin, tetracycline and talc following chest tube drainage and a meta-analysis of relative benefit of bleomycin and tetracycline as sclerosing agents were performed to determine the optimal approach to malignant pleural effusion (MPE). Fifty patients were randomized to receive bleomycin (n=16), tetracycline (n=19) or talc (n=16) following chest tube drainage. Treatment groups were balanced for pretreatment characteristics. The study was ended prematurely because of the removal of parenteral tetracycline from the market. Overall, 52% of randomized patients had successful control of effusion 30 days after sclerosis. There were no differences between any of the three treatment groups in terms of 30 day control of effusion, overall survival (6 months), resclerosis rate, pain with sclerosis, fever, or duration of hospitalization (6 days). A meta-analysis was performed using the four previously reported trials of tetracycline vs. bleomycin and revealed a 20.6% advantage to the use of bleomycin (95% C.I. 7.9%-33.3%) (p=0.002). This phase III failed to demonstrate a significant difference between the three agents in terms of control of MPE at 30 days, side effects or survival. However, because of small sample size, this study lacks sufficient power to observe potentially clinically important differences between treatment groups. Inclusion of data from four previous trials in a meta-analysis showed that bleomycin may be superior. The median duration of hospitalization and the overall success rate of all three sclerosing agents in this study argue convincingly that new approaches to palliate MPE are needed.