Background: Video-assisted thoracoscopic surgery (VATS) involving wedge resection of bulla and lung biopsy can be done by two or three-port incisions. Controversy exists as to which approach is superior. We communicate our experience with two-port VATS for these procedures. Methods: We retrospectively analyzed the charts of all patients who underwent a VATS procedure by two-port incisions from July 2001 to July 2007 by two thoracic surgeons (S.C., S.C.) We included in the study all patients who underwent wedge resections for primary or secondary spontaneous pneumothorax and biopsies for pulmonary infiltrates and small nodules. Results: A total of 319 patients’ charts were examined, and 217 of whom had undergone two-port incisions fitted in the inclusion criteria. There were 136 (65.7%) males and 81 (37.3%) females with a mean age of 47 years. Pneumothorax was the main diagnosis for 98 (45%) patients, followed by pulmonary infiltrates for 69 (32%) patients and lung nodules for 50 (23%) patients. The mean operative time and the number of post-op days for chest tube removal and to discharge home in each group have also been recorded. There were few post-operative complications, such as 11 (5%) cases of persistent air leak, 11 (5%) cases of transient fever of unknown origin, 3 (1.4%) cases of pneumonia, 3 (1.4%) cases of bleeding within, one reoperated, and 1 (0.46%) case of C. difficile colitis. The 30-day mortality was 0%. Conclusion: The thoracoscopic (VATS) wedge biopsy via two-port incisions is a safe operation for patients presenting with pneumothorax or requiring a lung biopsy. A two-port approach seems to be a reasonable alternative to three-port incision procedures for these types of diagnosis, regarding post-operative pain and cosmetic benefits particularly for young patients.