Background Periodontal disease is a common dental problem. In Taiwan, about ninety percent of adults suffer from various forms of periodontal diseases. Early periodontal diseases may not have symptoms; when people start to develop signs or symptoms, they may have already suffer moderate or advanced periodontal diseases, resulting in subsequent tooth loss. Therefore, effective control and treatment for periodontal diseases is an important public health issue in many countries. Clinically, the extent of periodontal disease are usually measured by clinical attachment level (CAL) and probing pocket depths (PPD). Periodontal surgery is the main treatment for severe periodontal disease. There are two types of periodontal surgeries; one is traditional flap operation (FO), and the other is periodontal regeneration surgery. The most common periodontal regeneration surgeries are enamel matrix derivative (EMD) and guided tissue regeneration (GTR). Objectives As the cost of periodontal regeneration surgery is much greater than flap operation. Previous meta-analyses only compared one-year results after the periodontal surgeries. Therefore, the objectives of this study are: 1. To use longitudinal meta-analysis to compare the difference in the long-term treatment benefits between various periodontal regeneration surgeries and traditional flap surgery. 2. To investigate whether there is difference in the long-term effect of two common periodontal regeneration therapies, enamel matrix derivative and guided tissue regeneration surgery. Material and methods We conduct a systematic review to search for studies that compared the difference in PPD and CAL between periodontal regeneration surgeries. In addition, longitudinal meta-analysis and restricted cubic spline function are used to investigate the difference in clinical outcomes between the two periodontal surgeries. Results 1. The long-term results of clinical attachment level and probing pocket depth in each comparison displays the effect of periodontal regeneration surgeries are better than that of flap surgery. These additional effects last for more than five years, and maintain in 1 mm to 1.5 mm. 2. The difference between enamel matrix derivative and guided tissue regeneration is not significant either in clinical attachment level or probing pocket depth. 3. The trajectory of each comparison group shows small changes by assuming different correlations between outcomes reported at different time points Conclusion We used longitudinal meta-analysis and restricted cubic spline to investigate the differences in trajectory of the effect of periodontal surgeries. The long-term effects of periodontal regeneration surgeries are better than the those of flap surgery in long-term. In addition, there is no significant difference between enamel matrix derivative and guided tissue regeneration.