The purpose of this proof of principle trial was to assess whether conventional periodontal therapy and systemically administrated acetylsalicylic acid (ASA) are functionally synergistic when combined in the treatment of periodontitis. A total of 30 patients with untreated moderate to severe adult periodontitis were enrolled into the study and were given placebo q.i.d. between the baseline and 6-week examination, and acetylsalicylic acid (ASA) 500 mg q.i.d. between the 6-week and 12-week examinations. In addition, they received supra- and subgingival scaling in 1 quadrant after baseline examination and in 2 further randomly selected quadrants after the 6-week examination. The study design resulted in the following 4 therapies: (1) scaling plus ASA 500 mg q.i.d.; (2) scaling plus placebo q.i.d.; (3) ASA 500 mg q.i.d. alone; (4) placebo q.i.d. alone. Two-way analysis of variance showed functional synergism of ASA and scaling, resulting in a therapeutic efficacy approximately equivalent to the sum of each individual therapeutic efficacy (i.e., ASA alone and scaling alone) in reducing gingival inflammation and pocket probing depth over the 6-week observation period (interaction: p > 0.05). Only the effect of ASA was significant in reducing the concentration of elastase-alpha 1-proteinase inhibitor in gingival crevicular fluid (GCF E-alpha 1-PI) (p < 0.001), reduction in GCF E-alpha 1-PI concentrations by ASA may indicate a decreased risk in periodontal disease progression. The results suggest that the combination of therapies and their different mechanisms of action, i.e., reduction of bacterial plaque and inhibition of destructive components of the immune responses, may result in functionally synergistic therapeutic efficacies in patients with untreated adult periodontitis.