The intrapleural instillation of agents for pleural sclerosis has proved effective in preventing the reaccumulation of symptomatic malignant pleural effusions. Because manufacture of the most popular agent, tetracycline, was recently discontinued, a preliminary study was undertaken to evaluate an alternative agent, doxycycline, for treating symptomatic malignant pleural effusions. From November 1991 to September 1992, 21 patients with symptomatic malignant pleural effusions have undergone overnight chest tube drainage followed by intrapleural instillation of 10 mL 1% lidocaine and then doxycycline, 500 mg in 30 mL 0.9% saline solution. The chest tube was clamped 2 hours with patient repositioning every 15 minutes. Tubes were removed when drainage was less than 50 mL/8 h. Of surviving patients, a complete objective response at 1 month was obtained in 88% (15/17), who were free of a symptomatic or radiographic recurrence of the effusion. Complications included mild pain in 23% (5/21), moderate pain requiring analgesics in 19% (4/21), and mild fever in 5% (1/21). There were no treatment-related deaths. The mean time for chest tube removal was 1.7 +/- 0.7 days after the last treatment. Based on this preliminary study, we conclude that doxycycline is a highly effective agent for the palliative treatment of symptomatic malignant pleural effusions. Its safety profile and efficacy compare favorably with those of tetracycline and other agents used for pleural sclerosis.