Background: Most general thoracic surgeons use double-lumen endotracheal tube (DLET) anesthesia for all video-assisted thoracoscopic surgery (VATS). We evaluated a single-lumen endotracheal tube (SLET) for VATS for drainage of pleural effusions and pleural biopsies. Methods: A consecutive series of patients with recurrent pleural effusions underwent VATS using an SLET and only one incision. Operations were accomplished via one 2-cm incision using a 5-mm rigid thoracoscope and mediastinoscopic biopsy forceps for directed pleural biopsies. A working area was accomplished with low tidal volumes. Results: There were 376 patients (191 women). The indications for VATS were a nondiagnosed or benign pleural effusion in 294 patients, and a malignant effusion in 82 patients. Two hundred eight patients underwent biopsy of the parietal pleura, and mean operative time was 17 min. Adequate visibility was obtained in all. When compared to preoperative cytology, VATS was more sensitive (45% compared to 99%, p < 0.001), had a higher negative predictive value (56% compared to 99%, p < 0.001), and was more accurate (67% compared to 99%, p < 0.001). Forty-seven percent of patients with a history of cancer had false-negative preoperative cytology results. Complications occurred in seven patients (2%), and there were three operative deaths (none related to the operative procedure). Conclusion: VATS using SLET and only one incision is possible, and it affords excellent visualization of the pleural space, allowing pleural biopsies and talc insufflation. It avoids the risk, time, and cost of a DLET. It is significantly more sensitive and accurate than preoperative cytology, and it should be considered as the diagnostic and therapeutic procedure of choice in patients with recurrent pleural effusions.