The aim of this study was to compare surgical treatment of periodontal intra-bony defects (IBD) with or without the adjunct of enamel matrix derivative (EMD) in terms of acute-phase responses in healthy patients. Thirty-eight periodontitis-affected subjects, one IDB each, were randomized to minimally invasive periodontal surgery (MIS) with or without EMD. Periodontal parameters were recorded at baseline and 6-months. Blood samples were collected at baseline, 1, 7 and 180days after treatment. At 24hr, the group treated MIS with EMD showed lower values of C-reactive protein (CRP; p<.01) as no inflammatory perturbation was noticed. Conversely, MIS group resulted in an acute inflammatory response at 24hr (p<.05) that regressed to its baseline values at day 7. The EMD group showed a higher number of cases without residual BOP or PPD≥5mm 6months after surgery (p<.05), and post-surgical gingival recession was lower (p<.05). The adjunctive application of EMD during surgical treatment resulted in a minor increase in serum CRP 24-hr after surgery. These findings suggest a possible systemic anti-inflammatory effect of EMD. Within its limitations, this pilot trial confirmed better clinical periodontal outcomes in the EMD group. NCT03590093.