Aim: This systematic review aimed to determine the optimum dose and duration of amoxicillin‐plus‐metronidazole prescribed as an adjunct to non‐surgical treatment of periodontitis.

Methods: Electronic searching identified 376 records, of which 18 were eligible blinded, randomized placebo‐controlled trials. The primary outcomes assessed were periodontal pocket depth and clinical attachment level at 3 months, and secondary outcomes were adverse events and compliance. Subgroup analyses were conducted to compare lower and higher doses, and 7‐ and 14‐day courses.

Results: Meta‐analysis showed a small beneficial effect of adjunctive amoxicillin‐plus‐metronidazole for each primary outcome, but there was <0.1 mm variation with antibiotic dose or duration. Risk differences for adverse events in the higher dose and longer duration groups were minimally greater (0.04 and 0.05, respectively), and there was one report of anaphylaxis; 1.3% of patients were not fully compliant.

Conclusion: There was no clinically meaningful difference between different doses or duration of amoxicillin‐plus‐metronidazole at 3 months post‐treatment. Without compelling evidence to suggest that any one regimen performed superiorly, principles of responsible antibiotic use generally recommend the highest dose for the shortest duration of time to reduce the risk of antibiotic resistance. Therefore, a 7‐day regimen of 500/500 mg or 500/400 mg of amoxicillin and metronidazole would be most appropriate.