Objectives: Amelogenins contribute to the early resolution of inflammation in periodontal lesions, which suggests their anti-inflammatory effect. Therefore, the main objective of this study was to compare surgical treatment of periodontal infrabony defects with and without the adjunct of an enamel matrix derivative (EMD) in terms of acute-phase responses, in systemically healthy patients. The primary outcome measure was the change of C Reactive Protein (CRP) at 24 hours after the surgery. Methods: The study was a randomized single-blind clinical trial with 2 treatment arms: surgical therapy with the adjunctive application of EMD and surgical therapy without the EMD, respectively. The study type was monocentric. The follow-up was 6 months. The patients were eligible if they were in a good health (ASA I) and without previous periodontal surgery done. Patients who reported current smoking over 20 cigarettes per day or pipe or cigar were excluded. Thirty-eight periodontitis patients with intrabony defects of ≥ 4 mm in vertical depth were randomly allocated to one of the two treatment arms. For randomization purposes, each patient received a code that corresponded to an assignment of the groups and was placed in a sealed envelope that was opened only at the time of the treatment. Clinical parameters were measured at baseline and at 6 months control. Following measurements were taken: periodontal pocket depth (PPD), clinical attachment level (CAL), recession. Systemic parameters were taken at baseline and at day 1, day 7 and day 180 after periodontal surgery. Blood sample analysis included lipid profile, CRP, fibrinogen, D-dimer, cystatin, glucose levels. Statistical analysis was performed with multivariate analysis of covariance and the level of significance was set at 0.05. Covariates included in the model were age, smoking and body mass index. Results: A total of 121 subjects were screened, 38 included and completed the study. A total number of 38 patients completed the study. There was similar sex distribution among participants, while the test group patients were younger (p0.05). All smokers belonged to the test group (n=2). The CRP values changed in both groups after periodontal surgical treatment. In the test group, the CRP increased from baseline values of 2.10 mg/L (95% CI: 0.56, 3.62) to 3.10 mg/L (95% CI: 1.57, 4.62) at day 1. In the control group, the CRP increased from 1.84 mg/L (95% CI: 0.44, 3.24) at baseline to 4.36 mg/L (95% CI: 2.99, 5.78) at day 1 (p0.05), resulting in a higher CRP values for the control group at day 1 when compared to test group (p=0.004). The CRP values decreased gradually in both groups, and this decrease was more pronounced for the control group, when compared to its day 1 values (p0.0001 vs. day 1). Fibrinogen levels increased at day 1 and decreased afterwards for both groups. In the test group, the baseline values of 295.63 mg/dL (95% CI: 260.46, 330.78) changed to 327.79 mg/dL (95% CI: 292.62, 362.96) at day 1. In the control group, the values of 275.47 mg/dL (95% CI: 246.33, 304.62) at baseline increased to 317.68 mg/dL (95% CI: 288.54,346.82) at day 1 (p0.0001 vs. baseline). Surgical treatment proved efficacious in both groups, since it resulted in reduction of all measured clinical parameters at 6 months (p0.01 vs. baseline). However, CAL gain was higher in the test group: 4.26 ± 2.182 mm versus 3.26 ± 2.207 mm in the control group. Conclusion: To the best of the authors knowledge, this is the first study assessing the systemic effect of regenerative surgery of periodontal infrabony defects. Our data show that the adjunction of EMD was associated with lower increase of CRP and fibrinogen in test group at day 1 after periodontal surgery, suggesting a possible systemic anti-inflammatory effect. This local and systemic effect of EMD can be of interest when surgically treating periodontitis patients with systemic comorbidities. More research is needed to gain further insight into present findings. The study was registered in ClinicalTrials.gov: NCT03590093. Keywords: periodontitis, enamel matrix derivative, EMD, C-reactive protein, CRP