Full-mouth scaling and root planing (FM-SRP) increases the systemic levels of inflammatory mediators via early inflammation but may be inhibited using an antimicrobial agent. This prospective intervention study evaluates the biological response and clinical effects of FM-SRP with and without systemically administered azithromycin (AZM). A multicenter parallel randomized controlled and open-label trial. A central randomization center used computer-generated tables to allocate treatments. Sixty-three patients with moderate to severe generalized periodontitis (New American Academy of Periodontology Classification: Stage3 or 4, Grade B) were randomly assigned to receive FM-SRP with AZM (test group, n = 32) or FM-SRP without AZM (control group, n = 31). Clinical parameters and body temperature were measured, and subgingival plaque, peripheral blood, and gingival crevicular fluid were collected before and after treatment. Periodontopathic bacteria and IgG titers were measured by gingival crevicular fluid and peripheral blood. High-sensitivity assays were used to analyze systemic and local inflammatory markers, such as endotoxin, high-sensitive CRP (hs-CRP), and six inflammatory cytokines. Follow-up 6 weeks. The total number of bacteria and the number of Porphyromonas gingivalis and Prevotella intermedia were significantly lower in the test group after FM-SRP. IgG titers for P gingivalis significantly decreased after FM-SRP with AZM, and the body temperature increased significantly after FM-SRP without AZM. In the control group, serum hs-CRP, IFN-γ, IL-12p70, and IL-6 were significantly increased one day after treatment, but subsequently decreased below the original numerical value. In the test group, only hs-CRP showed a significant increase. FM-SRP resulted in similar improvements in clinical parameters with and without the use of AZM. Inflammatory mediators showed no difference between the two groups after FM-SRP treatment. The use of AZM was effective in preventing the elevation of body temperature after FM-SRP. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.