AIM: To evaluate the effect of 3 or 7 days systemic administration of amoxicillin (AMX) and metronidazole (MET) or placebo as adjunct to non-surgical periodontal treatment in severe chronic periodontitis patients. METHODS: One hundred and two patients with severe chronic periodontitis [e.g. ≥1 site with probing pocket depth (PD) ≥ 6 mm per quadrant] were randomly divided into three equally sized groups and treated with either scaling and root planing within 24 h (SRP) + placebo (Group A) or SRP + AMX + MET (both 500 mg × 3 times daily) for 3 days (Group B) or SRP + AMX + MET (both 500 mg × 3 times daily) for 7 days (Group C). PD, clinical attachment level (CAL), bleeding on probing (BOP), full-mouth plaque scores (FMPS) and gingival bleeding index (GBI) were assessed prior to treatment (baseline), and at 3 and 6 months post-treatment. The primary outcome variable was the difference (Δ) in the number of sites with PD ≥ 6 mm. RESULTS: Ninety-one patients completed the study. At both 3 and 6 months, all three treatment protocols resulted in statistically significant improvements compared to baseline for all evaluated clinical parameters (p < 0.001). At 6 months, a statistically significantly greater reduction in the mean number of sites with PD ≥ 6 mm was observed in group B (28.62 ± 15.32 sites) and group C (30.45 ± 15.04 sites) compared to the placebo group (17.10 ± 14.68 sites). Furthermore, both the 3- and the 7-day antibiotic regimen resulted in statistically significantly higher clinical improvements compared to the placebo group (p < 0.05). CONCLUSION: The present findings indicate that in patients with severe chronic periodontitis, non-surgical periodontal therapy in conjunction with a 3 or 7 days systemic administration of AMX + MET may lead to significantly greater clinical improvements compared to non-surgical therapy alone.