It is estimated that over 100,000 patients require a pleurodesis in USA each year. Pleurodesis, the iatrogenic induction of pleural fibrosis to obliterate the pleural cavity, is the most effective way to prevent re-accumulation of pleural fluid. Currently used pleurodesing agents - talc, tetracycline derivatives and bleomycin - effect pleurodesis by inducing an acute pleural injury and inflammation, which eventually heals with fibrosis. Pleural inflammation is associated with side effects such as pain, fever and potentially fatal respiratory failure. There is thus a desperate need for development of novel agents. We have shown that a potent pro-fibrotic and anti-inflammatory cytokine, transforming growth factor (TGF)-β, can produce a pleurodesis, and circumvents the induction of pleural inflammation. In vitro, TGF-β2 stimulates collagen synthesis by pleural mesothelial cells, as well as suppresses their interleukin-8 production. In animal models, intrapleural TGF-β2 produces pleurodesis faster than talc and with less local inflammatory reaction. Unlike existing pleurodesing agents, TGF-β2 remains effective even with co-administration of systemic corticosteroids. TGF-β3 is equally effective as TGF-β2. A single intrapleural injection of TGF-β2 does not induce any acute physiological complications or extrapulmonary side effects. The use of TGF-β for pleurodesis should be further assessed in phase I clinical trials.