Background: Two-port (2P) and three-port (3P) video-assisted thoracoscopic surgery (VATS) are well-established surgical methods for the treatment of complicated spontaneous pneumothorax (SP). However, a comparison between both techniques, in terms of clinical outcomes in patients with secondary spontaneous pneumothorax (SSP), is unreported. The aim of this study was to evaluate and compare postoperative pain, as well as clinical outcome, following 2P and 3P VATS for SSP in our institution. Methods: Between January 2008 and December 2020, we retrospectively analyzed the data of 115 SSP patients treated by VATS in our institution. Fifty-two patients underwent 2P-VATS, while 63 patients were treated by 3P-VATS. The total dose of analgesic use per stay (opioid and non-opioid), length of hospital stay (LOS), operation time, total area of pleurectomy, recurrence rates and postoperative complications were compared between both groups. Results: The 3P-VATS group had a significantly higher total dose of analgesic use compared with the 2P-VATS patients. The LOS and mean operation time were significantly shorter in the 2P-VATS group. A larger area of pleurectomy was resected using 3P-VATS compared to 2P-VATS. The postoperative complications and recurrence of SSP during a median follow-up period of 76.5 months were similar in both groups. Conclusion: 2P-VATS is a safe surgical technique. It is associated with a short LOS and less postoperative pain, and, thus, low analgesic use.