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This study is aimed at evaluating the safety and efficacy of intrapleural tissue plasminogen activator (TPA) for complicated pleural effusions, including posttraumatic hemothorax.Data were retrospectively collected from hospitalized patients over a 4-year period (1999–2003) who were treated with intrapleural TPA after failing drainage by tube thoracostomy. Pre- and post-TPA imaging studies were reviewed and scored by a blinded radiologist.Forty-one consecutive patients with 42 effusions were identified with the following indications: 6 traumatic hemothoraces (14%), 22 loculated pleural effusions (52%), 2 line-associated hemothoraces (5%), and 12 empyemas (29%). Nine patients (22%) required operative drainage including two with posttraumatic hemothoraces. All patients managed nonoperatively demonstrated radiographic improvement after TPA administration. One patient (2.4%) developed hematuria, requiring transfusion. No trauma patient required TPA-related blood transfusion and no deaths were attributable to TPA therapy.Intrapleural TPA administration appears safe for use in complicated pleural effusions and may decrease the need for operative intervention.