We have reported previously that there is a high incidence of hemothorax and substantial mortality in rabbits that are given tetracycline derivatives intrapleurally. However, such complications have not been reported in humans when pleurodesis is attempted with tetracycline derivatives. One primary difference in the two situations is that a chest tube is placed only in humans. The objective of this study was to evaluate the hypothesis that chest tube placement would prevent the development of hemothoraces and lead to better pleurodesis in rabbits given doxycycline intrapleurally. Eighty New Zealand White male rabbits received doxycycline, 20 mg/kg, in a total volume of 2 mL. One half of the rabbits were randomized to receive a chest tube at the time of the injection and were subjected to pleural fluid aspiration twice daily. The remaining rabbits (control group) received no chest tube and no aspiration. Ten rabbits from each group were killed on days 4, 7, 14, and 28. The intrapleural injection of doxycycline induced the production of large exudative effusions. The insertion of chest tubes prevented the development of hemothorax (0/20 in chest tube group, 15/20 in control group, p<0.001). The insertion of chest tubes was also associated with a significant reduction in mortality and a significant improvement in pleurodesis. When pleurodesis is attempted in rabbits with intrapleural doxycycline, the insertion of a chest tube will prevent hemothorax and lead to a better pleurodesis.