Background and objective Some subjects with untreated peri- odontitis exhibit elevated levels of distinct inflammatory markers in serum. The aim of the study was to assess whether nonsurgical periodontal therapy changes the levels of these markers and lowers these peaks. Methods Forty periodontally diseased subjects received non- surgical periodontal therapy (full-mouth scaling and root planing within 48 h) with either adjunctive systemic amoxi- cillin and metronidazole (n= 19) or placebo (n= 21). Serum samples, obtained at baseline (BL) and 3 months after treat- ment (M3), were evaluated for 15 cytokines and 9 acute-phase proteins using the Bio-Plex bead array multianalyte detection system. For each analyte, peak values were defined as greater than the mean + 2 standard deviations (SD) of measurements found in 40 periodontally healthy persons. Proportions were compared using Fisher's exact test. Results At M3, a significantly better primary clinical outcome (persisting pockets of >4 mm with bleeding on probing) was obtained in patients treated with scaling and root planing plus antibiotics compared to those receiving placebo (3.3±5.1 vs. 6.8±7.8 pockets per patient, p<0.05). The levels of cytokines and acute-phase proteins of periodontitis patients were usually below the mean+2 SD threshold of healthy persons.However, values above threshold were found in some indi- viduals. Eleven patients showed a peak value of one analyte, and seven patients showed two peaks. In the remaining 12 patients, between three and ten analytes showed peak values. Therapy greatly reduced the number of subjects with four or more peaks (BL, 11 subjects; M3, 1 subject, p=0.003). With regards to the reduction of peaks, no specific benefit of ad- junctive antibiotics could be seen. Conclusion Subjects with untreated periodontitis may show high peaks for several inflammatory markers in serum simul- taneously. Nonsurgical periodontal treatment with or without antibiotics reduced most of these peak levels.