© 2016 Australian Dental AssociationBackground: There are insufficient guidelines for the use of adjunctive systemic antibiotics for patients with periodontal disease. The aim of this study was to compare clinical outcomes for patients with moderate-advanced chronic periodontitis treated with: scaling and root planing (SRP), SRP with amoxicillin and metronidazole (A+M), SRP with Azithromycin (Az). Methods: Thirty-seven non-smokers with generalized moderate to advanced chronic periodontitis were divided into three treatment groups: SRP, A+M and Az. Patients received the medications after the last SRP session and were reviewed three months later. Changes in clinical parameters were compared between the groups. Separate analyses were executed for: ‘all sites’, ‘molar sites’, ‘sites with different PPD severities’ and ‘number of sites with shallow, moderate and deep PPD’. Results: The three groups exhibited improvements in most clinical parameters. At three months, A+M showed a higher reduction in PPD compared to Az in the ‘all sites analysis’. Molars exhibited better reduction in BOP and PPD with A+M than SRP. Pocket depth of the 4–6 mm category reduced more in the A+M than SRP. A+M experienced a higher increase in the number of sites with PPD 1–3 mm than Az. Conclusions: Adjunctive systemic antibiotics in the initial phase of treatment may result in improved clinical outcomes.